Pyrimidine-fused ring compounds

Abstract

A pyrido-ring compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and its use in the preparation of drugs for treating related diseases.

Description

[0001] This application claims the following priorities:

[0002] CN202010826692.0, with an application date of August 17, 2020;

[0003] CN202110873055.3, with an application date of July 30, 2021. Technical Field

[0004] The present invention relates to pyrimidine-fused ring compounds, and specifically discloses compounds represented by formula (III) or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their applications in the preparation of anti-cancer drugs. Background Art

[0005] Cyclin-dependent kinases (CDKs) are a class of cellular enzymes that play an important role in regulating the division and proliferation of eukaryotic cells. They are involved in physiological processes such as cell proliferation and transcription. Clinical studies have shown that the occurrence of various cancers is closely related to cell cycle regulation. For example, the activation of proto-oncogenes or the inactivation of tumor suppressor genes often leads to abnormal cell cycle regulation, resulting in unlimited cell proliferation and tumor formation. Therefore, inducing cell cycle arrest can effectively inhibit tumor growth. According to the different functions of CDKs, they can be divided into two major categories: 1) One type of CDK is involved in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.; 2) Another type of CDK is involved in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK10, CDK11, etc. Among them, CDK4 / 6 is a key regulator of the cell cycle. The CDK4 / 6-cyclin D complex formed by its binding to cyclin D can phosphorylate a series of substrates including retinoblastoma protein (Rb). After phosphorylation, Rb is released and activates the pre-bound transcription factor E2F, causing the cell to transition from the G1 phase to the S phase, leading to cell growth and proliferation, and ultimately resulting in tumor formation. CDK4 / 6 is abnormally activated in a variety of tumors. Therefore, inhibiting the activity of CDK4 / 6 can theoretically inhibit tumor growth.

[0006] CDK4 / 6 inhibitors are the rising anti-cancer "magic drugs" in the past three to five years, and are rapidly changing the treatment landscape of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative (HR+HER2-) advanced breast cancer, effectively overcoming or delaying the emergence of endocrine resistance and gaining more survival time for advanced patients. However, like other kinases, the effects of these inhibitors may be limited by the development of primary and secondary resistance over time. An important reason for resistance to CDK4 / 6 inhibitors is the amplification or overexpression of Cyclin E (J. Clin. Oncol. 2019, 37, 1148-1150). In ER+ breast cancer cells, high expression of Cyclin E2 is often accompanied by resistance to hormone therapy (Mol. Cancer Ther., 2012, 11, 1488-1499), and the amplification or overexpression of Cyclin E is closely related to the poor prognosis of breast cancer (N. Engl. J. Med, 2002, 347, 1566-1575). In HER2+ breast cancer, the amplification of Cyclin E has also been reported to contribute to resistance to trastuzumab (Proc. Natl. Acad. Sci., 2011, 108, 3671-3676). There are also reports that overexpression of Cyclin E also plays an important role in the progression of triple-negative breast cancer (Breast Care, 2011, 6, 273-278) or inflammatory breast cancer (Oncotarget, 2017, 8, 14897-14911). Therefore, the development of CDK2 inhibitors may benefit patients with primary and secondary resistance to CDK4 / 6 inhibitors.

[0007] Currently, there are a few small molecule inhibitors with CDK2 activity in the clinical research stage. For example, dinaciclib can inhibit CDK1, CDK2, CDK5 and CDK9, and is undergoing clinical development for breast cancer and blood cancer. In addition, seliciclib can inhibit CDK2, CDK7 and CDK9, and is being combined with chemotherapy drugs for clinical research in advanced solid tumors. However, so far, no CDK2 inhibitors have been approved, so there is an urgent need to develop novel, safe and effective CDK2 inhibitors that can treat a variety of cancers, especially small molecule inhibitors that selectively target CDK2, which may have better safety. Summary of the invention

[0008] The present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in,

[0011] Ring A is selected from C 3～8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3～8 cycloalkenyl, and 3- to 10-membered heterocycloalkenyl, and the C 3～8 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 3～8 cycloalkenyl, and 3- to 10-membered heterocycloalkenyl are each independently optionally substituted with 1, 2, or 3 R a substituents;

[0012] W is selected from and R5;

[0013] Ring B is selected from C 3～8 cycloalkyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl, and the C 3～8 cycloalkyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R b substituents;

[0014] X is selected from C(R c ) and N;

[0015] Y is selected from a single bond, -NH-, and -O-;

[0016] L is selected from a single bond and -S(=O)2-;

[0017] R1 is selected from H, halogen, C 1～3 alkyl, C 1～3 alkoxy, and -C(=O)-C 1～3 alkyl, and the C 1～3 alkyl, C 1～3 alkoxy, and -C(=O)-C 1～3 alkyl are each independently optionally substituted with 1, 2, or 3 R d substituents;

[0018] R2 and R3 are each independently selected from H, halogen, OH, CN, NH2, and C 1～8 alkyl, and the C 1～8 alkyl is optionally substituted with 1, 2, or 3 R e substituents;

[0019] R4 is selected from NH2, -NH-C 1～6 alkyl, -NH(CN), -NH(OH), C 1～6 alkyl, -N(CN)-C 1～6 alkyl, and -N(OH)-C 1～6 alkyl, and the -NH-C 1～6 alkyl, C 1-6 alkyl, -N(CN)-C 1～6 alkyl, and -N(OH)-C 1～6The alkyl groups are each independently optionally substituted by 1, 2 or 3 Rs f ;

[0020] R5 is selected from C g alkyl groups optionally substituted by 1, 2 or 3 Rs 1～3 ;

[0021] R c is selected from H, F, Cl, Br, I and CH3;

[0022] R d are each independently selected from F, Cl, Br, I, CH3, OCH3, OH, NH2, CN, COOH;

[0023] R a , R b , R e and R f are each independently selected from F, Cl, Br, I, OH, CN, CH3, CH3CH2, CH3CH2CH2, CH(CH3)2, OCH3, OCF3, CHF2, CH2F and NH2;

[0024] R g are each independently selected from F, Cl, Br, I, OH, CN and CH3;

[0025] The 3- to 10-membered heteroalkyl groups, 5- to 6-membered heteroaryl groups and 3- to 10-membered heteroalkenyl groups each contain 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.

[0026] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0027]

[0028] wherein,

[0029] Ring A is selected from C 3～8 cycloalkyl, 3- to 10-membered heteroalkyl, C 3～8 cycloalkenyl and 3- to 10-membered heteroalkenyl, and the C 3～8 cycloalkyl, 3- to 10-membered heteroalkyl, C 3～8 cycloalkenyl and 3- to 10-membered heteroalkenyl are each independently optionally substituted by 1, 2 or 3 Rs a ;

[0030] Ring B is selected from C 3～8 cycloalkyl and 3- to 10-membered heteroalkyl, and the C 3～8 cycloalkyl and 3- to 10-membered heteroalkyl are optionally substituted by 1, 2 or 3 Rs b ;

[0031] X is selected from C(R c ) and N;

[0032] Y is selected from a single bond, -NH-, and -O-;

[0033] L is selected from a single bond and -S(=O)2-;

[0034] R1 is selected from H, halogen, C 1～3 alkyl, C 1～3 alkoxy, and -C(=O)-C 1～3 alkyl, wherein the C 1～3 alkyl, C 1～3 alkoxy, and -C(=O)-C 1～3 alkyl are each independently optionally substituted with 1, 2, or 3 R d substituents;

[0035] R2 and R3 are each independently selected from H, OH, CN, NH2, and C 1～8 alkyl, wherein the C 1～8 alkyl is optionally substituted with 1, 2, or 3 R e substituents;

[0036] R4 is selected from -NH(CN), -NH(OH), C 1～6 alkyl, -N(CN)-C 1～6 alkyl, and -N(OH)-C 1～6 alkyl, wherein the C 1-6 alkyl, -N(CN)-C 1～6 alkyl, and -N(OH)-C 1～6 alkyl are each independently optionally substituted with 1, 2, or 3 R f substituents;

[0037] R c is selected from H, F, Cl, Br, I, and CH3;

[0038] R d are each independently selected from F, Cl, Br, I, CH3, OCH3, OH, NH2, CN, COOH;

[0039] R a 、R b 、R e and R f are each independently selected from F, Cl, Br, I, OH, CN, CH3, CH3CH2, CH3CH2CH2, CH(CH3)2, OCH3, OCF3, CHF2, CH2F, and NH2.

[0040] The 3- to 10-membered heteroalkyl and 3- to 10-membered heteroalkenyl each contain 1, 2, or 3 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N.

[0041] In some embodiments of the present invention, the above R1 is selected from H, Cl, CHF2, CF3 and CH3, and other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above R1 is selected from H, Cl, CHF2 and CH3, and other variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above R2 and R3 are each independently selected from H, OH, CN, NH2 and C 1～8 alkyl, and the C 1～8 alkyl is optionally substituted by 1, 2 or 3 R e substituents.

[0044] In some embodiments of the present invention, the above R2 and R3 are each independently selected from H, F, Cl, OH and CH3, and other variables are as defined in the present invention, and other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above R2 and R3 are each independently selected from H, OH and CH3, and other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the above R4 is selected from CH3, NH2 and -NH(CH3), and other variables are as defined in the present invention.

[0047] In some embodiments of the present invention, the above R4 is selected from CH3, and other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, the above X is selected from CH, CF, CCl, CBr, CCH3 and N, and other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, the above X is selected from CH, CCl, CBr, CCH3 and N, and other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the above ring A is selected from 5- to 6-membered heteroalkyl, and the 5- to 6-membered heteroalkyl is optionally substituted by 1, 2 or 3 R a substituents, and other variables are as defined in the present invention.

[0051] In some embodiments of the present invention, the above ring A is selected from piperidinyl, and the piperidinyl is optionally substituted by 1, 2 or 3 R a substituents, and other variables are as defined in the present invention.

[0052] In some embodiments of the present invention, the above ring A is selected from

[0053] In some embodiments of the present invention, the above ring A is selected from Other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above-mentioned ring B is selected from C 5～6 cycloalkyl, 5- to 6-membered hetero cycloalkyl, and 5- to 6-membered heteroaryl, and the C 5～6 cycloalkyl, 5- to 6-membered hetero cycloalkyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with 1, 2, or 3 R b substituents, and other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above-mentioned ring B is selected from cyclopentyl, pyrrolidinyl, and pyrazolyl, and the cyclopentyl, pyrrolidinyl, and pyrazolyl are each independently optionally substituted with 1, 2, or 3 R b substituents, and other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, the above-mentioned ring B is selected from C 3～6 cycloalkyl, and the C 5～6 cycloalkyl is optionally substituted with 1, 2, or 3 R b substituents, and other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, the above-mentioned ring B is selected from cyclopentyl, and the cyclopentyl is optionally substituted with 1, 2, or 3 R b substituents, and other variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the above-mentioned structural unit is selected from Other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the above-mentioned structural unit is selected from Other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the above-mentioned structural unit -Y-W is selected from Other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, the above-mentioned structural unit -Y-W is selected from Other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the above-mentioned structural unit is selected from Other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the above-mentioned R5 is selected from Other variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the above-mentioned compound is selected from

[0065]

[0066] wherein, R1, R2, R3, R4, R5, X, Y and ring A are as defined in the present invention.

[0067] In some embodiments of the present invention, the above-mentioned compound is selected from

[0068]

[0069] wherein, R1, R2, R3, R4, R5 and R c are as defined in the present invention.

[0070] In some embodiments of the present invention, the above-mentioned compound is selected from

[0071]

[0072] wherein, R1, R2, R3, R4, X, Y and ring A are as defined in the present invention.

[0073] In some embodiments of the present invention, the above-mentioned compound is selected from

[0074]

[0075] wherein, R1, R2, R3, R4, X and Y are as defined in the present invention.

[0076] The present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

[0077]

[0078]

[0079] In some embodiments of the present invention, the above-mentioned compound is selected from

[0080]

[0081]

[0082] In some embodiments of the present invention, the above-mentioned compound is selected from

[0083]

[0084]

[0085] The present invention also provides the use of the above compounds in the preparation of drugs for treating breast cancer.

[0086] Some embodiments of the present invention are formed by any combination of the above variables.

[0087] Technical effects

[0088] The compounds of the present invention have a significant inhibitory effect on CDK2.

[0089] Definitions and explanations

[0090] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this text, it is intended to refer to the corresponding commodity or its active ingredient.

[0091] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0092] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents found in the present invention with relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, where the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, where the organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanedioic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and similar acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can thus be converted into either base or acid addition salts.

[0093] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing acidic or basic groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with stoichiometric appropriate bases or acids in water, organic solvents, or a mixture of both.

[0094] The compounds of the present invention can exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0095] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0096] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely.

[0097] Unless otherwise specified, the term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0098] Unless otherwise specified, "(D)" or "(+)" indicates dextrorotation, "(L)" or "(-)" indicates levorotation, and "(DL)" or "(±)" indicates racemic.

[0099] Unless otherwise specified, the absolute configuration of a stereocenter is represented by a solid wedge bond and a dashed wedge bond the relative configuration of a stereocenter is represented by a solid straight bond and a dashed straight bond a wavy line represents a solid wedge bond or a dashed wedge bond or a wavy line represents a solid straight bond or a dashed straight bond

[0100] The compounds of the present invention may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0101] Unless otherwise specified, the terms "enriched in one isomer", "isomer enrichment", "enriched in one enantiomer", or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of this isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0102] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0103] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which employs a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of a carbamate from an amine).

[0104] "Optional" or "optionally" means that the subsequently described event or circumstance may but does not necessarily occur, and the description includes both the case where the described event or circumstance occurs and the case where the described event or circumstance does not occur.

[0105] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on an aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on the basis of what is chemically achievable.

[0106] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted with 0 - 2 R's, the group may optionally be substituted with up to two R's, and R has independent options in each case. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in a stable compound.

[0107] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond, and -C0alkyl-A means that the structure is actually -A.

[0108] When the number of a substituent is 0, it means that the substituent is absent, such as -A-(R)0 means that the structure is actually -A.

[0109] When a substituent is vacant, it means that the substituent is absent, such as when X is vacant in A-X, it means that the structure is actually A.

[0110] When one of the variables is selected from single bonds, it means that the two groups it connects are directly linked. For example, when L in A-L-Z represents a single bond, it indicates that the structure is actually A-Z.

[0111] When the bond of a substituent can cross-link to more than one atom on a ring, this substituent can bond to any atom on this ring. For example, the structural unit indicates that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituent does not specify which atom it connects to the group to be substituted, this substituent can bond through any of its atoms. For example, the pyridyl group as a substituent can connect to the group to be substituted through any carbon atom on the pyridine ring.

[0112] When the listed linking group does not specify its linking direction, the linking direction is arbitrary. For example, in which the linking group L is -M-W-, at this time -M-W- can connect ring A and ring B in the same direction as the reading order from left to right to form or can connect ring A and ring B in the opposite direction to the reading order from left to right to form The combination of the said linking group, substituent and / or its variant is only allowed if such a combination results in a stable compound.

[0113] Unless otherwise specified, when a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups through chemical bonds. The chemical bond connecting the site to other groups can be represented by a straight solid line bond a straight dashed line bond or a wavy line For example, the straight solid line bond in -OCH3 indicates connection to other groups through the oxygen atom in this group; the straight dashed line bond in indicates connection to other groups through both ends of the nitrogen atom in this group;

[0114] Unless otherwise specified, the number of atoms in a ring is usually defined as the ring member count. For example, "5- to 7-membered ring" refers to a "ring" composed of 5 to 7 atoms arranged in a ring.

[0115] Unless otherwise specified, the term "halogen" or "halogen atom" itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.

[0116] Unless otherwise specified, the term "C 1～8"Alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 8 carbon atoms. The C 1～8 alkyl includes C 1～6 、C 1～5 、C 1～4 、C 1～3 、C 1～2 、C 2～6 、C 2～4 、C8, C7, C6 and C5 alkyls, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1～8 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl, etc.

[0117] Unless otherwise specified, the term "C 1～6 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1～6 alkyl includes C 1～5 、C 1～4 、C 1～3 、C 1～2 、C 2～6 、C 2～4 、C6 and C5 alkyls, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1～6 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0118] Unless otherwise specified, the term "C 1～3 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1～3 alkyl includes C 1～2 and C 2～3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1～3 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0119] Unless otherwise specified, the term "C 1～6 alkoxy" denotes those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1～6 alkoxy includes C 1～4 、C1～3 , C 1～2 , C 2～6 , C 2～4 , C6, C5, C4, and C3 alkoxy groups, etc. C 1～6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, and neopentyloxy), hexyloxy, etc.

[0120] Unless otherwise specified, the term "C 1～3 alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms that are connected to the rest of the molecule through an oxygen atom. The C 1～3 alkoxy groups include C 1～2 , C 2～3 , C3, and C2 alkoxy groups, etc. C 1～3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.

[0121] Unless otherwise specified, the term "halogen" or "halogens" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine atoms.

[0122] Unless otherwise specified, "C 3～8 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which includes monocyclic and bicyclic systems, where the bicyclic system includes spiro, fused, and bridged rings. The C 3～8 cycloalkyl groups include C 3～6 , C 3～5 , C 4～8 , C 4～6 , C 4～5 , C 5～8 or C 5～6 cycloalkyl groups, etc.; it can be monovalent, divalent, or polyvalent. C 3～8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, etc.

[0123] Unless otherwise specified, "C 3～6 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system. The C 3～6 cycloalkyl groups include C 3～5 , C 4～5 and C 5～6 cycloalkyl groups, etc.; it can be monovalent, divalent, or polyvalent. C 3～6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0124] Unless otherwise specified, "C 3～8 cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms containing at least one carbon-carbon double bond, which includes monocyclic and bicyclic systems, where the bicyclic system includes spiro, fused, and bridged rings, and any ring of this system is non-aromatic. The C 3～8 cycloalkenyl includes C 3～6 , C 3～5 , C 4～10 , C 4～8 , C 4～6 , C 4～5 , C 5～8 or C 5～6 cycloalkenyl, etc.; it can be monovalent, divalent or polyvalent. C 3～8 Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc.

[0125] Unless otherwise specified, the term "3- to 10-membered heterocycloalkyl" alone or in combination with other terms separately represents a saturated cyclic group consisting of 3 to 10 ring atoms, where 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., C(=O), NO and S(O)p, p is 1 or 2). It includes monocyclic, bicyclic and tricyclic systems, where the bicyclic and tricyclic systems include spiro, fused and bridged rings. In addition, for this "3- to 10-membered heterocycloalkyl", the heteroatom can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 3- to 10-membered heterocycloalkyl includes 3- to 8-membered, 3- to 6-membered, 3- to 5-membered, 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl, etc. Examples of 3- to 10-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0126] Unless otherwise specified, the term "5- to 6-membered heterocycloalkyl" alone or in combination with other terms separately represents a saturated cyclic group composed of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remaining are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic systems, and the bicyclic system includes spiro, fused, and bridged rings. In addition, with respect to this "5- to 6-membered heterocycloalkyl", the heteroatom can occupy the connection position of the heterocycloalkyl to the rest of the molecule. The 5- to 6-membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyls. Examples of 5- to 6-membered heterocycloalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxolanyl, dithiolanyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, etc.

[0127] Unless otherwise specified, the term "3- to 10-membered heteroalkenyl" alone or in combination with other terms separately represents a partially unsaturated cyclic group composed of 3 to 10 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remaining are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic systems, and the bicyclic and tricyclic systems include spiro, fused, and bridged rings, and at least one of these systems is non-aromatic. In addition, with respect to this "3- to 10-membered heteroalkenyl", the heteroatom can occupy the connection position of the heteroalkenyl to the rest of the molecule. The 3- to 10-membered heteroalkenyl includes 3- to 8-membered, 3- to 6-membered, 3- to 5-membered, 4- to 6-membered, 4- to 5-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heteroalkenyls, etc. Examples of 3- to 10-membered heteroalkenyls include, but are not limited to

[0128] Unless otherwise specified, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl group" of the present invention can be used interchangeably. The term "5- to 6-membered heteroaryl group" refers to a monocyclic group composed of 5 to 6 ring atoms having a conjugated π-electron system, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms can be optionally oxidized (i.e., C(=O), NO, and S(O)p, where p is 1 or 2). The 5- to 6-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5- to 6-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0129] The solvents used in the present invention are commercially available.

[0130] IC 50 refers to the concentration of a certain reagent corresponding to 50% maximum inhibition when using the reagent.

[0131] The present invention uses the following abbreviations: Pd(t-Bu3P)2 represents bis(tri-tert-butylphosphine)palladium; POCl3 represents phosphorus oxychloride; DMAc represents N,N'-dimethylacetamide; m-CPBA represents meta-chloroperbenzoic acid; DMSO represents dimethyl sulfoxide; DMF represents N,N'-dimethylformamide; NMP represents N-methylpyrrolidone; DIPEA represents N,N'-diisopropylethylamine; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; p-TSA represents p-toluenesulfonic acid; TBSCl represents tert-butyldimethylsilyl chloride; Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocene palladium chloride; Rh(PPh3)3Cl represents tris(triphenylphosphine)rhodium chloride; DAST represents diethylaminosulfur trifluoride; AIBN represents azobisisobutyronitrile; NMO represents N-methylmorpholine N-oxide.

[0132] Compounds are named according to the conventional naming principles in the art or using software naming, and commercially available compounds use the supplier catalog names.

[0133] Unless otherwise specified, the ratios of solvents used in the silica gel column chromatography described in the present invention are all volume ratios. Detailed Description of the Invention

[0134] The present invention will be described in detail below through examples, but this does not mean any adverse limitation to the present invention. The compounds of the present invention can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and the equivalent replacement methods well known to those skilled in the art. The preferred embodiments include, but are not limited to, the examples of the present invention. It will be obvious to those skilled in the art to make various changes and improvements to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0135] Synthesis of Intermediate A:

[0136]

[0137] The first step:

[0138] Compound A1 (1.5 g, 5.70 mmol, 1 eq), compound A2 (1.69 g, 8.55 mmol, 1.5 eq), sodium carbonate (1.21 g, 11.40 mmol, 2 eq), Pd(t-Bu3P)2 (145.68 mg, 285.05 μmol, 0.05 eq) were dissolved in a mixed solution of water (5 mL) and tetrahydrofuran (15 mL). The resulting mixed solution was purged with nitrogen three times and then reacted at 65 °C for 16 h. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (50 mL). The obtained organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound A3. LCMS (ESI) m / z: 255.1 (M+1).

[0139] Step 2:

[0140] Ammonia (7 mol / L, 30 mL, 47.60 eq) was introduced into a methanol (30 mL) solution of compound A3 (1.06 g, 4.41 mmol, 1 eq). The mixture was stirred and reacted at 85 °C in a sealed tube for 16 h. The reaction solution was concentrated under reduced pressure to obtain compound A4. LCMS (ESI) m / z: 240.1 (M+1).

[0141] Step 3:

[0142] p-TSA (282 mg, 1.64 mmol, 0.437 eq) was added to a toluene (20 mL) solution of compound A4 (897 mg, 3.75 mmol). The mixture was reacted at 90 °C for 1.5 h. The residue was obtained by concentration under reduced pressure and washed with petroleum ether to obtain intermediate A. LCMS (ESI) m / z: 194.1 (M+1).

[0143] Example 1: Preparation of Compound 1

[0144]

[0145] Step 1:

[0146] Intermediate A (890 mg, 4.61 mmol, 1 eq) was dissolved in POCl3 (10 mL). The resulting mixed solution was purged with nitrogen three times and then reacted at 70 °C for 1.5 h. The reaction solution was added dropwise to a mixture of water (50 mL) and ethyl acetate (50 mL). The obtained organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1a. LCMS (ESI) m / z: 211.8. (M+1).

[0147] Step 2:

[0148] To a solution of Compound 1a (685 mg, 3.24 mmol, 1 equiv) and Compound 1b (559.08 mg, 4.85 mmol, 1.5 equiv) in DMAc (10 mL) was added triethylamine (982.40 mg, 9.71 mmol, 1.35 mL, 3 equiv). The mixture was reacted at 130 °C for 16 h. The reaction solution was added to a mixture of water (50 mL) and ethyl acetate (50 mL). The obtained organic phase was washed with saturated brine (50 mL × 5), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain Compound 1c. LCMS (ESI) m / z: 291.2 (M+1).

[0149] The third step:

[0150] At 0 °C, m-CPBA (647.77 mg, 3.75 mmol, 2.0 equiv) was added to a solution of Compound 1c (545 mg, 1.88 mmol, 1 equiv) in dichloromethane (10 mL). The reaction was carried out at 15 °C for 16 h. A mixed solution of water (50 mL) and ethyl acetate (50 mL) was added to the reaction solution. The obtained organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by preparative thin layer chromatography silica gel plate (petroleum ether / ethyl acetate = 1 / 2) to obtain Compound 1d. LCMS (ESI) m / z: 323.1 (M+1).

[0151] The fourth step:

[0152] To a solution of Compound 1d (255.80 mg, 793.47 μmol, 1 equiv) in DMSO (5 mL) was added Compound 1e (255.55 mg, 1.19 μmol, 1.5 equiv, hydrochloride) and DIPEA (512.75 mg, 3.97 mmol, 5 equiv). The reaction solution was reacted at 60 °C for 23 h. LC-MS showed that 30% of the raw material remained and the target product was detected to have been formed. The above reaction solution was continued to react at 60 °C for 2 h. The reaction solution was added to a mixture of water (50 mL) and ethyl acetate (50 mL), and the layers were separated. The obtained organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase A: 10 mmol / L aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; gradient elution: 20%-50%, 10 min) to obtain Compound 1. 11H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.69 (d, J = 6.2 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 5.29 (d, J = 3.6 Hz, 1H), 4.12 - 4.09 (m, 2H), 3.81 - 3.78 (m, 2H), 3.00 (m, 2H), 2.85 (s, 3H), 2.29 - 2.22 (m, 3H), 2.01 - 1.88 (m, 1H), 1.75 - 1.73 (m, 2H), 1.71 - 1.59 (m, 5H), 1.13 (s, 3H); LCMS (ESI) m / z: 421.3 (M + 1).

[0153] Example 2: Preparation of Compound 2

[0154]

[0155] First step:

[0156] Intermediate A (0.64 g, 3.31 mmol, 1 equiv) and NBS (648.47 mg, 3.64 mmol, 1.1 equiv) were dissolved in DMF (10 mL) solution, and the reaction was stirred at 25 °C for 0.5 h. The reaction solution was poured into water (30 mL), filtered, and the filter cake was dried to obtain Compound 2a. LCMS (ESI) m / z: 274.0 (M + 1).

[0157] Second step:

[0158] Compound 2a (0.53 g, 1.95 mmol, 1 equiv) was dissolved in POCl3 (16.50 g, 107.61 mmol, 10 mL, 55.25 equiv). The resulting mixed solution was purged with nitrogen three times and then reacted at 70 °C for 1 h. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound 2b. LCMS (ESI) m / z: 292.0 (M + 1).

[0159] Third step:

[0160] To a solution of compound 2b (0.68 g, 2.34 mmol, 1 equiv) and compound 1b (404.30 mg, 3.51 mmol, 1.5 equiv) in DMAc (10 mL) was added triethylamine (710.43 mg, 7.02 mmol, 3 equiv). The mixture was reacted at 130 °C for 12 h. Water (10 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 2c. LCMS (ESI) m / z: 371.0 (M+1).

[0161] Step 4:

[0162] At 0 °C, m-CPBA (1.23 g, 5.69 mmol, 2.5 equiv) was added to a solution of compound 2c (0.84 g, 2.27 mmol, 1 equiv) in dichloromethane (10 mL). The reaction was carried out at 25 °C for 3 h. Aqueous saturated sodium sulfite solution (5 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative thin-layer silica gel plate (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 2d. LCMS (ESI) m / z: 403.3 (M+1).

[0163] Step 5:

[0164] To a solution of compound 2d (0.2 g, 498.41 μmol, 1 equiv) and compound 1e (160.52 mg, 747.61 μmol, hydrochloride, 1.5 equiv) in DMSO (5 mL) was added DIPEA (322.07 mg, 2.49 mmol, 5 equiv). The reaction was carried out at 60 °C for 12 h. Water (5 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative high performance liquid chromatography (column: Xtimate C18 150*40mm*10μm; mobile phase A: water (containing 0.05% ammonia); mobile phase B: acetonitrile; gradient elution: 34% - 64%, 10 min) to obtain compound 2. LCMS (ESI) m / z: 501.1 (M+1); 11H NMR (400 MHz, CD3OD) δ 9.07 (s, 1H), 7.70 (s, 1H), 4.62 (br s, 2H), 4.26 - 4.09 (m, 2H), 3.75 (br d, J = 11.6 Hz, 2H), 3.02 (br t, J = 11.4 Hz, 2H), 2.90 (s, 3H), 2.35 (br d, J = 8.1 Hz, 1H), 2.18 (br d, J = 9.9 Hz, 2H), 1.92 - 1.75 (m, 5H), 1.22 (s, 3H).

[0165] Example 3: Preparation of Compound 3

[0166]

[0167] First step:

[0168] Intermediate A (0.5 g, 2.59 mmol, 1 eq) and NCS (380.09 mg, 2.85 mmol, 1.1 eq) were dissolved in DMF (5 mL) solution, and the reaction was stirred at 25 °C for 0.5 h. The reaction solution was poured into water (30 mL), filtered, and the filter cake was dried to obtain Compound 3a. LCMS (ESI) m / z: 228.0 (M+1).

[0169] Second step:

[0170] Compound 3a (0.15 g, 658.85 mmol, 1 eq) was dissolved in POCl3 (9.9 g, 64.57 mmol, 6 mL, 98 eq), and the resulting mixed solution was purged with nitrogen three times and then reacted at 70 °C for 1.5 h. Water (10 mL) was added to quench the reaction solution, and the resulting mixture was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound 3b. LCMS (ESI) m / z: 246.0 (M+1).

[0171] Third step:

[0172] To a DMAc (5 mL) solution of Compound 3b (0.11 g, 446.94 μmol, 1 eq) and Compound 1b (51.48 mg, 446.94 μmol, 1 eq) was added triethylamine (135.68 mg, 1.34 mmol, 3 eq), and the mixture was reacted at 130 °C for 12 h. Water (10 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound 3c. LCMS (ESI) m / z: 325.2 (M+1).

[0173] Step 4:

[0174] At 0 °C, m-CPBA (467.50 mg, 2.71 mmol, 2 eq) was added to a solution of compound 3c (0.44 g, 1.35 mmol, 1 eq) in dichloromethane (5 mL). The reaction was carried out at 25 °C for 3 h. Aqueous saturated sodium sulfite solution (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative TLC silica gel plate (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 3d. LCMS (ESI) m / z: 357.1 (M+1).

[0175] Step 5:

[0176] DIPEA (307.87 mg, 2.38 mmol, 5 eq) was added to a solution of compound 3d (0.17 g, 476.42 μmol, 1 eq) and compound 1e (153.44 mg, 714.63 μmol, 1.5 eq, hydrochloride) in DMSO (5 mL). The reaction was carried out at 60 °C for 5 h. Water (5 mL) was added to dilute the reaction mixture, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative HPLC (column: Xtimate C18 150*40mm*10μm; mobile phase A: water (containing 0.05% ammonia); mobile phase B: acetonitrile; gradient elution: 33% - 63%, 10 min) to obtain compound 3. LCMS (ESI) m / z: 455.1 (M+1); 1 H NMR (400 MHz, CD3OD) δ 9.15 (s, 1H), 7.60 (s, 1H), 4.61 (br s, 2H), 4.22 - 4.08 (m, 2H), 3.82 - 3.69 (m, 2H), 3.02 (br t, J = 10.8 Hz, 2H), 2.90 (s, 3H), 2.39 - 2.29 (m, 1H), 2.18 (br dd, J = 2.6, 12.9 Hz, 2H), 1.85 - 1.70 (m, 5H), 1.22 (s, 3H).

[0177] Example 4: Preparation of Compound 4

[0178]

[0179] Step 1:

[0180] To a solution of Compound 1a (728 mg, 3.44 mmol, 1 equiv) and Compound 4a (585.7 mg, 6.88 mmol, 678.67 μL, 2 equiv) in DMAc (10 mL) was added potassium carbonate (1.43 g, 10.32 mmol, 3 equiv), and the resulting mixture was reacted at 120 °C for 16 h. The reaction solution was added to a mixed solution of ethyl acetate (150 mL) and water (150 mL), and the obtained organic phase was washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Compound 4b. LCMS (ESI) m / z: 261.4 (M+1).

[0181] Step 2:

[0182] At 0 °C, m-CPBA (0.838 g, 3.89 mmol, 2.2 equiv) was added to a solution of Compound 4b (0.46 g, 1.77 mmol, 1 equiv) in dichloromethane (5 mL), and the reaction was carried out at 25 °C for 2 h. The reaction solution was added to a mixed solution of ethyl acetate (50 mL) and water (50 mL), and the obtained organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained residue product was purified by preparative thin-layer chromatography silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to obtain Compound 4c. LCMS (ESI) m / z: 293.1 (M+1).

[0183] Step 3:

[0184] To a solution of Compound 4c (0.255 g, 872.22 μmol, 1 equiv) and Compound 1e (280 mg, 1.3 μmol, 1.5 equiv, hydrochloride) in DMSO (3 mL) was added DIPEA (338.19 mg, 2.62 mmol, 3 equiv), and the reaction was carried out at 80 °C for 18 h. The reaction solution was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase A: 10 mmol / L aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; gradient elution: 35%-65%, 10 min) to obtain Compound 4. LCMS (ESI) m / z: 391.3 (M+1); 11H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.82 (d, J = 5.60 Hz, 1H), 6.68 (d, J = 5.60 Hz, 1H), 6.29 (d, J = 5.60 Hz, 1H), 5.21 (d, J = 5.60 Hz, 1H), 4.44 - 4.49 (m, 1H), 4.1 - 4.21 (m, 1H), 3.76 - 3.80 (m, 2H), 3.50 (s, 1H), 3.00 - 3.04 (m, 2H), 2.85 (s, 3H), 2.18 - 2.26 (m, 5H), 1.72 - 1.78 (m, 6H).

[0185] Example 5: Preparation of Compound 5

[0186]

[0187] First Step:

[0188] Dissolve Compound A1 (6 g, 22.80 mmol, 1 eq), Compound 5a (21.33 g, 228.04 mmol, 28.03 mL, 10 eq) and DBU (34.72 g, 228.04 mmol, 34.37 mL, 10 eq) in methanol (40 mL). The resulting mixed solution is placed in a sealed tube and reacted at 90 °C for 18 h. The reaction solution is concentrated under reduced pressure. The obtained residue is diluted with ethyl acetate (200 mL). The organic phase is washed with aqueous hydrochloric acid solution with pH 3 (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated. The obtained residue product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Compound 5b. LCMS (ESI) m / z: 290.0 (M+1).

[0189] Second Step:

[0190] Dissolve Compound 5b (2.6 g, 9.02 mmol, 1 eq), trans-bis[2-(di-o-tolylphosphino)benzyl] palladium diacetate (169.20 mg, 180.45 mmol, 0.02 eq) and DIPEA (4.66 g, 36.09 mmol, 6.29 mL, 4 eq) in DMAc (50 mL). The resulting mixed solution is placed in a sealed tube and reacted at 150 °C for 18 h. LCMS shows that the raw material has completely reacted. The reaction solution is added to a mixed solution of water (150 mL) and dichloromethane (150 mL). The layers are separated. The organic phase is washed with water (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated. The obtained residue product is purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain Compound 5c. LCMS (ESI) m / z: 208.6 (M+1).

[0191] Step 3:

[0192] Dissolve compound 5c (0.96 g, 2.96 mmol, 1 equiv) in POCl3 (25 mL), and react the resulting mixed solution at 70 °C for 3 h. Concentrate the reaction solution, add saturated sodium bicarbonate solution (250 mL) and ethyl acetate (250 mL) to the obtained residue, and extract with ethyl acetate (250 mL). Wash the combined organic phases with saturated brine (250 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The obtained residue product is purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 5d. LCMS (ESI) m / z: 226.4 (M+1).

[0193] Step 4:

[0194] Add triethylamine (589.57 mg, 5.83 mmol, 810.96 μL, 5 equiv) to a solution of compound 5d (263 mg, 1.17 mmol, 1 equiv) and compound 1b (201.31 mg, 1.75 mmol, 1.5 equiv) in NMP (3 mL), and react the mixture at 130 - 150 °C for 44 h. Dilute the reaction solution with water (150 mL) and extract with ethyl acetate (150 mL). Wash the combined organic phases with water (150 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The obtained residue is purified by silica gel chromatography plate (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 5e. LCMS (ESI) m / z: 305.2 (M+1).

[0195] Step 5:

[0196] Add m-CPBA (0.15 g, 0.87 mmol, 2.2 equiv) to a solution of compound 5e (0.12 g, 0.39 mmol, 1 equiv) in dichloromethane (3 mL), and react the reaction at 25 °C for 2 h. Add the reaction solution to a mixed solution of water (50 mL) and ethyl acetate (50 mL), wash the obtained organic phase with water (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. The obtained residue product is purified by preparative silica gel plate (petroleum ether / ethyl acetate = 1 / 2) to obtain compound 5f. LCMS (ESI) m / z: 337.2 (M+1).

[0197] Step 6:

[0198] To a solution of compound 5f (51 mg, 151.6 μmol, 1 equiv) and compound 1e (65.1 mg, 303.20 μmol, 1.5 equiv, hydrochloride) in DMSO (1 mL) was added DIPEA (97.97 mg, 758.01 mmol, 5 equiv), and the reaction was carried out at 100 °C for 72 h. The reaction solution was purified by preparative high performance liquid chromatography (column: Xtimate C18 150*40mm*10μm; mobile phase A: water (containing 0.05% ammonia); mobile phase B: acetonitrile; gradient elution: 27% - 57%, 10 min) to obtain compound 5. 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.70 (d, J = 6.0 Hz, 1H), 6.74 (d, J = 6.0 Hz, 1H), 6.38 (d, J = 2.8 Hz, 1H), 5.39 (d, J = 7.6 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.81 - 3.78 (m, 2H), 3.00 (m, 2H), 2.85 (s, 3H), 2.29 - 2.01 (m, 3H), 1.89 (m, 1H), 1.76 - 1.74 (m, 2H), 1.73 - 1.65 (m, 6H), 1.14 (s, 3H); LCMS (ESI) m / z: 435.2 (M+1).

[0199] Example 6: Preparation of Compound 6

[0200]

[0201] First Step:

[0202] Compound A1 (10 g, 38.01 mmol, 1 equiv), compound 6a (15.01 g, 45.61 mmol, 1.2 equiv), and Pd(t-Bu3P)2 (971.17 mg, 1.90 mmol, 0.05 equiv) in DMF (100 mL) were heated to 130 °C and stirred for 2 h. The reaction mixture was cooled to 20 °C and potassium fluoride (7 g) was added, and the resulting mixture was stirred at 20 °C for 15 min. The reaction mixture was filtered, water (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (100 mL * 2). The combined organic phases were washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 5 / 1) to obtain compound 6b. 11H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 4.04 - 3.97 (m, 3H), 2.65 - 2.55 (m, 3H), 2.13 (s, 3H). LCMS (ESI) m / z: 223.4 (M+1).

[0203] Step 2:

[0204] A mixed solution of acetone (120 mL) and water (30 mL) containing compound 6b (5 g, 22.50 mmol, 1 equiv), mercuric sulfate (6.67 g, 22.50 mmol, 1 equiv) and sulfuric acid (12 mol / L, 3.75 mL, 2 equiv) was heated to 80 °C and stirred for 14 h. The reaction mixture was concentrated, water (100 mL) was added to the resulting residue, and the mixture was filtered. The filtrate was extracted with dichloromethane (100 mL × 5). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative high performance liquid chromatography (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase A: water (containing 0.05% hydrochloric acid); mobile phase B: acetonitrile; gradient elution: 0% - 30%, 18 min) to obtain compound 6c. LCMS (ESI) m / z: 227.0 (M+1); 1 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 4.29 - 4.13 (m, 2H), 2.64 (s, 3H), 2.39 (s, 3H).

[0205] Step 3:

[0206] At -30 °C, ammonia gas (5.96 g, 350.00 mmol, 31.68 equiv) was bubbled into ethanol (50 mL) to obtain an ammonia / ethanol solution (7 mol / L, 50 mL). Compound 6c (2.5 g, 11.05 mmol, 1 equiv) was added to the above ammonia / ethanol solution, and the mixture was placed in a 30 mL pressure bottle and heated to 130 °C (oil bath temperature) and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to obtain compound 6d. LCMS (ESI) m / z: 208.1 (M+1).

[0207] Step 4:

[0208] A solution of compound 6d (1 g, 4.83 mmol, 1 equiv) in POCl3 (10 mL) was stirred at 50 °C for 0.5 h. The reaction mixture was diluted with ethyl acetate (50 mL), and the resulting mixture was slowly added dropwise to a stirred mixture of saturated sodium bicarbonate (100 mL) and ethyl acetate (50 mL). The organic phase was washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative thin-layer chromatography silica gel plate (petroleum ether / ethyl acetate = 2 / 1) to give compound 6e. LCMS (ESI) m / z: 226.8 (M+1).

[0209] Step 5:

[0210] A solution of compound 6e (0.1 g, 443.07 μmol, 1 equiv), compound 1b (56.13 mg, 487.38 μmol, 1.1 equiv) and triethylamine (89.67 mg, 886.14 μmol, 123.34 μL, 2 equiv) in DMAc (2 mL) was heated to 120 °C and stirred for 13 h. The reaction solution was poured into ice water (5 mL), stirred for 15 min, and extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by preparative thin-layer chromatography silica gel plate (petroleum ether / ethyl acetate = 3 / 1) to give compound 6f. LCMS (ESI) m / z: 305.1 (M+1).

[0211] Step 6:

[0212] A solution of compound 6f (0.1 g, 328.50 μmol, 1 equiv) and m-CPBA (146.72 mg, 722.71 μmol, 85% purity, 2.2 equiv) in dichloromethane (5 mL) was stirred at 20 °C for 2 h. The reaction mixture was quenched with 10% aqueous sodium sulfite solution (10 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL×5). The organic phase was concentrated, and the resulting residue was purified by preparative thin-layer chromatography silica gel plate (petroleum ether / ethyl acetate = 1 / 1) to give compound 6g. LCMS (ESI) m / z: 336.9 (M+1).

[0213] Step 7:

[0214] A DMSO solution (2 mL) of Compound 6 (70 mg, 208.08 μmol, 1 eq), Compound 1e (49.15 mg, 228.89 μmol, 1.1 eq, hydrochloride), and DIPEA (134.46 mg, 1.04 mmol, 181.22 μL, 5 eq) was heated to 100 °C and stirred for 16 h. LC-MS showed that approximately 62% of the starting material remained and approximately 20% of the product was formed. The reaction mixture was stirred at 100 °C for 3 h. LC-MS showed that approximately 58% of the starting material remained and approximately 22% of the product was formed. The reaction mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (column: Waters Xbridge 150*25 mm*5 μm; mobile phase A: water (containing 0.05% ammonia); mobile phase B: acetonitrile; gradient elution: 100%, 8 min) to obtain Compound 6. LCMS (ESI) m / z: 435.2 (M+1); 1 1H NMR (400 MHz, CD3OD) δ 8.88 (s, 1H), 6.67 (s, 1H), 4.60 (s, 2H), 4.19 - 4.05 (m, 2H), 3.77 - 3.67 (m, 2H), 3.11 - 2.97 (m, 2H), 2.89 (s, 3H), 2.41 - 2.28 (m, 4H), 2.23 - 2.12 (m, 2H), 2.03 - 1.66 (m, 7H), 1.16 (s, 3H).

[0215] Example 7: Preparation of Compound 7 and Compound 8

[0216]

[0217] Compound 6 (80 mg, 173.14 μmol) was subjected to SFC (column: DAICEL CHIRALPAK AD-H (250 mm*30 mm, 5 μm); mobile phase A: carbon dioxide; mobile phase B: ethanol containing 0.1% ammonia; gradient elution: 30% - 30%, 4 min) to obtain Compound 7 (retention time: 1.706 min) and Compound 8 (retention time: 1.831 min). The data characterization is as follows:

[0218] 1) Compound 7 (retention time: 1.706 min): LCMS (ESI) m / z: 435.3 (M+1); 11H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 6.73 (s, 1H), 4.76 - 4.62 (m, 1H), 4.24 - 4.07 (m, 2H), 3.81 - 3.68 (m, 2H), 3.02 (br t, J = 10.8 Hz, 2H), 2.89 (s, 3H), 2.43 - 2.29 (m, 4H), 2.16 - 2.15 (m, 2H), 2.00 (dt, J = 7.6, 3.1 Hz, 1H), 1.95 - 1.79 (m, 4H), 1.76 - 1.64 (m, 2H), 1.19 (s, 3H);

[0219] 2) Compound 8 (Retention time: 1.831 min): LCMS (ESI) m / z: 435.3 (M + 1); 1 1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 6.73 (s, 1H), 4.69 - 4.62 (m, 1H), 4.16 - 4.10 (m, 2H), 3.76 - 3.73 (m, 2H), 3.05 - 3.03 (br t, J = 10.4 Hz, 2H), 2.89 (s, 3H), 2.40 - 2.35 (m, 4H), 2.19 - 2.15 (m, 2H), 1.90 (m, 1H), 1.87 - 1.85 (m, 4H), 1.74 - 1.70 (m, 2H), 1.19 (s, 3H).

[0220] Example 8: Preparation of Compound 9

[0221]

[0222] The first step:

[0223] A solution of compound 9a (500 mg, 2.35 mmol, 1 equiv), compound 1b (297.87 mg, 2.59 mmol, 1.1 equiv) and triethylamine (356.87 mg, 3.53 mmol, 490.89 μL, 1.5 equiv) in acetonitrile (15 mL) was heated to 80 °C and stirred for 4 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9b. LCMS (ESI) m / z: 292.0 (M + 1).

[0224] The second step:

[0225] A solution of compound 9b (0.7 g, 2.40 mmol, 1 equiv) and m-CPBA (1.22 g, 6.01 mmol, 85% purity, 2.5 equiv) in dichloromethane (20 mL) was stirred at 20 °C for 2 h. Saturated sodium sulfite (15 mL) solution was added to the above reaction solution, and it was stirred for 15 min, and then extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by preparative thin-layer chromatography silica gel plate (ethyl acetate) to obtain compound 9c. LCMS (ESI) m / z: 324.5 (M+1).

[0226] The third step:

[0227] A solution of compound 9c (80 mg, 247.39 μmol, 1 equiv), compound 1e (58.43 mg, 272.13 μmol, 1.1 equiv, hydrochloride) and DIPEA (95.92 mg, 742.18 μmol, 129.27 μL, 3 equiv) in DMSO (3 mL) was heated to 80 °C and stirred for 10 h. The reaction solution was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase A: 10 mmol / L aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; gradient elution: 11% - 41%, 10 min) to obtain compound 9. 1 H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.29 (s, 1H), 6.58 (br s, 1H), 6.08 (br s, 1H), 5.38 (br s, 1H), 4.92 - 4.54 (m, 1H), 4.15 (ddd, J = 10.1, 8.5, 4.8 Hz, 1H), 4.07 - 3.92 (m, 1H), 3.72 (br d, J = 11.6 Hz, 2H), 2.99 - 2.85 (m, 2H), 2.77 (s, 3H), 2.36 - 2.22 (m, 1H), 2.14 (br dd, J = 12.9, 2.8 Hz, 2H), 2.03 - 1.92 (m, 1H), 1.90 - 1.77 (m, 3H), 1.70 - 1.55 (m, 2H), 1.08 (s, 3H). LCMS (ESI) m / z: 422.3 (M+1).

[0228] Example 9: Preparation of compound 10

[0229]

[0230] The first step:

[0231] Compound 10a (5 g, 59.44 mmol, 5.26 mL, 1 eq) was added to a solution of acetonitrile (50 mL) along with NBS (10.58 g, 59.44 mmol, 1 eq) and p-TSA (1.02 g, 5.94 mmol, 0.1 eq), and the mixture was stirred at 25 °C for 16 h. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain compound 10b. 1 H NMR (400 MHz, CDCl3) δ 4.17 (dd, J = 6.2, 4.7 Hz, 1H), 2.41 - 2.25 (m, 2H), 2.23 - 2.07 (m, 3H), 2.03 - 1.86 (m, 1H)

[0232] Step 2:

[0233] Compound 10b (1 g, 5.18 mmol, 1 eq), intermediate A (2.53 g, 15.53 mmol, 3 eq), and potassium carbonate (1.43 g, 10.35 mmol, 2 eq) were added to DMF (10 mL), and the resulting reaction solution was stirred at 20 °C for 16 h. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, and the mixture was poured into a separatory funnel for liquid separation. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The obtained organic phase was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 10c. LCMS (ESI) m / z: 276.2 (M+1); 1 H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.94 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 5.6 Hz, 1H), 5.63 (dd, J = 10.5, 8.6 Hz, 1H), 2.63 (s, 3H), 2.61 - 2.52 (m, 1H), 2.45 - 2.31 (m, 2H), 2.24 - 2.11 (m, 2H), 2.00 - 1.85 (m, 1H).

[0234] Step 3:

[0235] Under nitrogen protection at 0 °C, sodium borohydride (82.44 mg, 2.18 mmol, 1.5 eq) was added to a methanol (10 mL) solution of compound 10c (0.4 g, 1.45 mmol, 1 eq), and the reaction was carried out for 0.5 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and concentrated under reduced pressure. Water (10 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (10 mL × 4). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 10d.

[0236] Step 4:

[0237] A dichloromethane (10 mL) solution of compound 10d (300 mg, 1.07 mmol, 1 eq) and activated manganese dioxide (933.61 mg, 10.74 mmol, 10 eq) was heated to 40 °C and stirred for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography silica gel plate (ethyl acetate) to obtain compound 10e.

[0238] Step 5:

[0239] A dichloromethane (10 mL) solution of compound 10e (0.25 g, 901.42 μmol, 1 eq) and m-CPBA (427.77 mg, 1.98 mmol, purity: 80%, 2.2 eq) was stirred at 25 °C for 1 h. LCMS showed that the raw material had reacted completely and the target product had been formed. The reaction mixture was washed successively with 10% aqueous sodium sulfite solution (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL), and the organic phase was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography silica gel plate (ethyl acetate) to obtain compound 10f. LCMS (ESI) m / z: 310.1 (M+1)

[0240] Step 6:

[0241] A DMSO (1 mL) solution of compound 10f (15 mg, 48.49 μmol, 1 eq), compound 1e (15.62 mg, 72.74 μmol, 1.5 eq, hydrochloride) and DIPEA (31.34 mg, 242.45 μmol, 42.23 μL, 5 eq) was heated to 100 °C and stirred for 14 h. The reaction mixture was filtered, and the filtrate was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase A: 10 mmol / L aqueous ammonium bicarbonate solution; mobile phase B: acetonitrile; gradient elution: 15% - 45%, 10 min) to obtain compound 10. LCMS (ESI) m / z: 408.3 (M+1); 11H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.87 (d, J = 5.5 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H), 5.41 - 5.33 (m, 1H), 4.37 (q, J = 4.9 Hz, 1H), 4.24 - 4.06 (m, 1H), 3.82 (br d, J = 12.0 Hz, 2H), 2.98 (br t, J = 10.6 Hz, 2H), 2.85 (s, 3H), 2.37 - 2.20 (m, 3H), 2.07 - 1.88 (m, 5H), 1.74 - 1.66 (m, 4H).

[0242] Example 10: Preparation of Compound 11

[0243]

[0244]

[0245] The first step:

[0246] To a solution of Compound 11a (15 g, 182.70 mmol, 15.31 mL, 1 equiv) in acetonitrile (200 mL) was added pyridine N-oxide (20.85 g, 219.24 mmol, 1.2 equiv). The resulting reaction solution was cooled to 0 °C, and NBS (34.14 g, 191.84 mmol, 1.05 equiv) was added portionwise. Then the resulting reaction solution was stirred at 25 °C for 16 h. 10% Aqueous sodium sulfite solution (50 mL) was added to the above reaction solution, and the resulting mixture was concentrated under reduced pressure to remove acetonitrile. The aqueous phase was extracted with ethyl acetate (300 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain Compound 11b. 1 1H NMR (400 MHz, CDCl3) δ 7.83 - 7.75 (m, 1H), 2.75 - 2.67 (m, 2H), 2.58 - 2.48 (m, 2H).

[0247] The second step:

[0248] To a solution of compound 11b (20 g, 124.23 mmol, 1 equiv) in methanol (200 mL) was added cerium(III) chloride (33.68 g, 136.65 mmol, 8.59 mL, 1.1 equiv). The resulting reaction solution was cooled to 0 °C, and sodium borohydride (5.64 g, 149.07 mmol, 1.2 equiv) was added portionwise. The reaction solution was stirred at 25 °C for 16 h. Saturated aqueous ammonium chloride (100 mL) was added to the above reaction solution, and the resulting mixture was concentrated under reduced pressure to remove methanol. The aqueous phase was extracted with ethyl acetate (200 mL), and after liquid separation, the organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain compound 11c. 1 H NMR (400 MHz, CDCl3) δ 6.20 - 5.98 (m, 1H), 4.80 - 4.67 (m, 1H), 2.50 - 2.28 (m, 3H), 1.98 - 1.81 (m, 1H).

[0249] Step 3:

[0250] A solution of compound 11c (14.3 g, 87.72 mmol, 1 equiv) in dichloromethane (150 mL) was cooled to 0 °C. Imidazole (11.94 g, 175.45 mmol, 2 equiv) was added, and then tert-butyldimethylsilyl chloride (TBSCl) (13.22 g, 87.72 mmol, 10.75 mL, 1 equiv) was added portionwise. The resulting reaction solution was stirred at 25 °C for 16 h. The reaction solution was washed with water (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether) to obtain compound 11d. 1 H NMR (400 MHz, CDCl3) δ 5.98 - 5.77 (m, 1H), 4.67 - 4.49 (m, 1H), 2.35 - 2.25 (m, 1H), 2.21 - 2.02 (m, 2H), 1.75 - 1.63 (m, 1H), 0.83 - 0.77 (s, 9H), 0.05 - -0.05 (m, 6H).

[0251] Step 4:

[0252] Cool the solution of compound 11d (7.5 g, 27.05 mmol, 1 equiv) in tetrahydrofuran (50 mL) to -78 °C, slowly add dropwise butyllithium (2.5 M, 14.07 mL, 1.3 equiv), and stir at -78 °C for 30 minutes. Slowly add dropwise 11e (5.54 g, 29.75 mmol, 6.07 mL, 1.1 equiv) to the above reaction solution, and then stir the resulting mixture at -78 °C for 30 minutes. Quench the reaction solution with ammonium chloride (2 M, 20 mL), extract the aqueous phase with ethyl acetate (100 mL), and concentrate the organic phase. The obtained residue is purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1) to obtain compound 11f. 1 H NMR (400 MHz, CDCl3) δ 6.56 - 6.48 (m, 1H), 4.97 - 4.82 (m, 1H), 2.45 (m, 1H), 2.24 - 1.96 (m, 2H), 1.66 - 1.47 (m, 1H), 1.16 - 1.14 (m, 12H), 0.80 - 0.77 (m, 9H), 0.01--0.01 (m, 6H).

[0253] Step 5:

[0254] Cool the solution of compound 1 (2.0 g, 10.35 mmol, 1 equiv) in tetrahydrofuran (20 mL) to 0 °C, add sodium hydride (827.97 mg, 20.70 mmol, purity: 60%, 2 equiv) portionwise, stir at 0 °C for 30 minutes, add ditrifluoromethanesulfonanilide (4.44 g, 12.42 mmol, 1.2 equiv) portionwise, and then stir at 0 - 25 °C for 1.5 hours. Quench the reaction with 10% aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (100 mL), then wash with water (30 mL), dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, and then purify by silica gel column chromatography (petroleum ether:ethyl acetate = 20 / 1 to 10 / 1) to obtain compound 11f. LCMS (ESI) m / z: 326.2 (M+1).

[0255] Step 6:

[0256] Under nitrogen protection, a solution of water (2 mL) of Pd(dppf)Cl2 (224.94 mg, 307.42 μmol, 0.1 equiv) and potassium phosphate (1.96 g, 9.22 mmol, 3 equiv) was added to a solution of compound 11f (1.10 g, 3.38 mmol, 1.1 equiv) and compound 11g (1.0 g, 3.07 mmol, 1 equiv) in 1,4-dioxane (20 mL), and the resulting mixture was heated to 90 °C and stirred for 16 h. The reaction solution was concentrated, and the residue obtained was diluted with ethyl acetate (50 mL), then washed with water (20 mL), and the organic phase was concentrated. The residue obtained was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 11h. LCMS (ESI) m / z: 374.3 (M+1).

[0257] Step 7:

[0258] Rh(PPh3)3Cl (100.15 mg, 108.25 μmol, 1 equiv) was added to a solution of compound 11h (50 mg, 108.25 μmol, 1 equiv) in ethanol (10 mL), and the mixture was heated to 80 °C under a hydrogen pressure of 15 PSI and stirred for 1 h. The reaction solution was concentrated, and the residue obtained was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to obtain compound 11i. LCMS (ESI) m / z: 376.4 (M+1); 1 H NMR (400 MHz, CDCl3) δ 9.26 - 9.08 (m, 1H), 8.62 (d, J = 5.40 Hz, 1H), 7.48 (d, J = 5.52 Hz, 1H), 4.75 - 4.67 (m, 1H), 4.60 - 4.49 (m, 1H), 2.77 - 2.73 (m, 3H), 2.35 - 2.25 (m, 1H), 2.20 - 2.08 (m, 1H), 2.02 - 1.82 (m, 4H), 0.75 - 0.65 (m, 9H), 0.42 - 0.33 (m, 3H), -0.13 - -0.19 (m, 3H).

[0259] Step 8:

[0260] To a solution of compound 11i (100 mg, 266.24 μmol, 1 equiv) in dichloromethane (5 mL) was added m-CPBA (103.37 mg, 479.23 μmol, purity: 80%, 1.8 equiv). The resulting reaction mixture was stirred at 25 °C for 5 h. The reaction was quenched with saturated aqueous sodium sulfite solution (10 mL). The aqueous phase was extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 11j. LCMS (ESI) m / z: 408.4 (M+1).

[0261] Step 9:

[0262] To a solution of compound 11j (100 mg, 245.34 μmol, 1 equiv) in DMSO (1 mL) were added DIPEA (95.12 mg, 736.01 μmol, 128.20 μL, 3 equiv) and compound 1e (79.02 mg, 368.01 μmol, 1.5 equiv, hydrochloride). The resulting reaction mixture was heated to 100 °C and stirred for 1 h. The reaction was diluted with ethyl acetate (20 mL) and washed with water (5 mL×3). The organic phase was concentrated. The residue obtained was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 11k. LCMS (ESI) m / z: 506.5 (M+1).

[0263] Step 10:

[0264] To a solution of compound 11k (80 mg, 158.18 μmol, 1 equiv) in tetrahydrofuran (1 mL) was added hydrochloric acid (1.0 mol / L, 1 mL, 6.32 equiv). The reaction mixture was stirred at 25 °C for 30 min. 10% Aqueous sodium bicarbonate solution (5 mL) was added to the reaction, and then the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue obtained was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase A: water (containing 0.05% ammonia); mobile phase B: acetonitrile; gradient elution: 17%-45%, 10 min) to give compound 11. LCMS (ESI) m / z: 392.3; 11H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.38 (d, J = 5.40 Hz, 1H), 7.38 (d, J = 5.40 Hz, 1H), 5.66 - 5.41 (m, 1H), 4.97 - 4.77 (m, 1H), 4.43 - 4.30 (m, 1H), 4.07 - 3.81 (m, 4H), 3.05 - 2.95 (m, 2H), 2.86 (s, 3H), 2.53 - 2.33 (m, 2H), 2.17 (s, 3H), 1.86 (br s, 3H), 1.79 - 1.67 (m, 2H).

[0265] Example 11: Preparation of Compound 12 and Compound 13

[0266]

[0267] To a solution of Compound 11k (2.5 g, 4.85 mmol, 1 eq) in tetrahydrofuran (20 mL) was added hydrochloric acid solution (1.0 mol / L, 19.64 mL, 4.05 eq). The resulting mixture was stirred at 25 °C for 0.5 h. 10% Aqueous sodium bicarbonate solution (50 mL) was added to the reaction solution to quench the reaction, and then ethyl acetate (200 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (ethyl acetate), and the obtained racemate was separated and purified by SFC (column model: Chiralpak IG-3 50×4.6 mm I.D., 3 μm; mobile phase A: carbon dioxide, mobile phase B: methanol containing 0.05% diethylamine; gradient elution: mobile phase B / mobile phase A = 40%; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; pressure: 100 Bar) to obtain Compound 12 (retention time: 1.598 min) and Compound 13 (retention time: 2.130 min). The data characterization is as follows:

[0268] 1) Compound 12 (retention time: 1.598 min): LCMS (ESI) m / z: 392.4; 11H NMR (400 MHz, CDCl3) δ 9.06 - 8.92 (m, 1H), 8.29 (d, J = 5.4 Hz, 1H), 7.29 (d, J = 5.4 Hz, 1H), 5.52 - 5.31 (m, 1H), 4.84 - 4.64 (m, 1H), 4.29 - 4.21 (m, 1H), 4.03 - 3.68 (m, 4H), 3.00 - 2.84 (m, 2H), 2.80 - 2.72 (m, 3H), 2.40 - 2.19 (m, 2H), 2.17 - 1.99 (m, 3H), 1.96 - 1.71 (m, 3H), 1.69 - 1.58 (m, 2H).

[0269] 2) Compound 13 (Retention time: 2.130 minutes): LCMS (ESI) m / z: 392.3; 1 1H NMR (400 MHz, CDCl3) δ 9.18 - 9.00 (m, 1H), 8.38 (d, J = 5.4 Hz, 1H), 7.39 (d, J = 5.4 Hz, 1H), 5.71 - 5.36 (m, 1H), 4.40 - 4.29 (m, 1H), 4.12 - 3.80 (m, 4H), 3.06 - 2.93 (m, 2H), 2.89 - 2.80 (m, 3H), 2.50 - 2.34 (m, 2H), 2.29 - 2.10 (m, 3H), 2.07 - 1.82 (m, 3H), 1.79 - 1.68 (m, 2H).

[0270] Example 12: Preparation of Compound 14

[0271]

[0272] The first step:

[0273] Under nitrogen protection, a solution of compound 6e (875.83 mg, 3.88 mmol, 1 equiv), NBS (2.07 g, 11.64 mmol, 3 equiv) and AIBN (63.72 mg, 388.05 μmol, 0.1 equiv) in carbon tetrachloride (10 mL) was heated to 75 °C and stirred for 15 h. The reaction mixture was concentrated, and the residue obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to obtain compound 14a. LCMS (ESI) m / z: 306.0 (M + 1); 1 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.75 (s, 1H), 4.68 (s, 2H), 2.78 - 2.76 (m, 3H).

[0274] The second step:

[0275] To a solution of compound 14a (280 mg, 919.26 μmol, 1 equiv) in acetonitrile (10 mL) was added NMO (215.37 mg, 1.84 mmol, 194.03 μL, 2 equiv), and the resulting reaction mixture was stirred at 25 °C for 2 h. Sodium sulfite (0.5 g) was added to the above reaction mixture, and the mixture was stirred at 25 °C for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by preparative TLC silica gel plate (petroleum ether / ethyl acetate = 4 / 1) to give compound 14b. 1 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 9.28 (s, 1H), 8.23 (s, 1H), 2.71 (s, 3H). LCMS (ESI) m / z: 240.1 (M+1).

[0276] The third step:

[0277] Under nitrogen protection at 0 °C, DAST (73.98 mg, 458.94 μmol, 60.64 μL, 2.2 equiv) was slowly added dropwise to a solution of compound 14b (50 mg, 208.61 μmol, 1 equiv) in dichloromethane (1 mL). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was directly purified by preparative TLC silica gel plate (petroleum ether / ethyl acetate = 5 / 1) to give compound 14c. LCMS (ESI) m / z: 208.1 (M+1). 1 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.89 (s, 1H), 6.84 - 6.49 (m, 1H), 2.69 (s, 3H).

[0278] The fourth step:

[0279] A solution of compound 14c (10 mg, 38.21 μmol, 1 equiv), compound 14d (5.28 mg, 45.86 μmol, 1.2 equiv) and DIPEA (9.88 mg, 76.43 μmol, 13.31 μL, 2 equiv) in acetonitrile (1 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated, water (5 mL) and ethyl acetate (5 mL) were added to the residue obtained. After liquid separation, the aqueous phase was extracted with ethyl acetate (5 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 14e. LCMS (ESI) m / z: 341.1 (M+1).

[0280] The fifth step:

[0281] To a solution of compound 14e (15 mg, 44.07 μmol, 1 equiv) in dichloromethane (3 mL) was added m-CPBA (20.91 mg, 96.95 μmol, purity: 80%, 2.2 equiv), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was washed successively with aqueous 10% sodium sulfite solution (5 mL) and saturated aqueous sodium bicarbonate solution (5 mL × 2). The organic phase was concentrated under reduced pressure to give compound 14f. LCMS (ESI) m / z: 373.1 (M+1).

[0282] Step 6:

[0283] A solution of compound 14f (13 mg, 34.91 μmol, 1 equiv), compound 1e (8.99 mg, 41.89 μmol, 1.2 equiv, hydrochloride) and DIPEA (13.54 mg, 104.73 μmol, 18.24 μL, 3 equiv) in DMSO (1 mL) was stirred at 100 °C for 4 h. The reaction mixture was filtered, and the filtrate was purified by preparative high performance liquid chromatography (column model: Waters Xbridge 150*25mm*5μm; mobile phase A: water containing 0.05% ammonia; mobile phase B: acetonitrile; gradient elution: 28% - 58%, 7 min) to give compound 14. LCMS (ESI) m / z: 471.3 (M+1); 1 H NMR (400 MHz, CD3OD) δ 9.01 (s, 1H), 7.11 (s, 1H), 6.79 - 6.38 (m, 1H), 4.25 (t, J = 8.6 Hz, 1H), 4.21 - 4.11 (m, 1H), 3.79 - 3.72 (m, 2H), 3.08 - 2.99 (m, 2H), 2.90 (s, 3H), 2.44 - 2.29 (m, 1H), 2.22 - 2.12 (m, 2H), 2.04 - 1.93 (m, 1H), 1.90 - 1.67 (m, 6H), 1.37 - 1.27 (m, 1H), 1.19 (s, 3H).

[0284] Example 13: Preparation of Compound 15

[0285]

[0286] Step 1:

[0287] To a mixed solution of compound A1 (10 g, 38.01 mmol, equivalent) and compound 15a (8.89 g, 45.61 mmol, 1.2 equivalents) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium carbonate (8.06 g, 76.01 mmol, 2 equivalents). The reaction solution was purged with nitrogen, and then (t-Bu3P)2PdCl2 (971.17 mg, 1.90 mmol, 0.05 equivalent) was added. The resulting reaction solution was heated to 65 °C and stirred for 16 hours. The reaction solution was diluted with ethyl acetate (200 mL) and water (100 mL) respectively. After separation of the organic phase, it was concentrated to dryness. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 15b. LCMS (ESI) m / z: 252.0 (M+1).

[0288] Step 2:

[0289] A mixture of compound 15b (6 g, 23.88 mmol, 1 equivalent), potassium carbonate (3.30 g, 23.88 mmol, 1 equivalent) and potassium fluoride (4.16 g, 71.60 mmol, 3 equivalents) in ethanol (30 mL) and water (30 mL) was heated to 80 °C and stirred for 16 hours. Ethanol was removed by concentration, and then the mixture was extracted with ethyl acetate (100 mL). The organic phase was discarded. The aqueous phase was adjusted to pH 1 - 2 with hydrochloric acid (10 mol / L), and a solid precipitated. It was filtered, and the filter cake was dried to obtain compound 15c. LCMS (ESI) m / z: 210.0 (M+1).

[0290] Step 3:

[0291] A reaction solution of compound 15c (1.0 g, 4.73 mmol, 1 equivalent) and phosphorus pentachloride (1.08 g, 5.21 mmol, 1.1 equivalents) in POCl3 (10 mL) was stirred at 20 °C for 2 hours. The reaction solution was heated to 70 °C and stirred for 16 hours. POCl3 was removed by concentration to dryness. The resulting residue was diluted with ethyl acetate (50 mL) and slowly added to a 5% aqueous sodium carbonate solution (50 mL). The insoluble black oil was removed by filtration. The separated organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 15d. LCMS (ESI) m / z: 245.9 (M+1); 1 H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 7.59 (s, 1H), 2.67 (s, 3H).

[0292] Step 4:

[0293] To a solution of Compound 15d (500 mg, 2.03 mmol, 1 equiv) in acetonitrile (10 mL) was added Compound 14d (350.97 mg, 3.05 mmol, 1.5 equiv) and DIPEA (525.13 mg, 4.06 mmol, 707.72 μL, 2 equiv). The resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give Compound 15e. LCMS (ESI) m / z: 325.2 (M+1); 1 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.19 - 7.11 (m, 1H), 7.04 (s, 1H), 4.84 (s, 1H), 4.38 - 4.23 (m, 1H), 2.66 (s, 3H), 2.29 - 2.13 (m, 1H), 1.85 - 1.56 (m, 5H), 1.19 (s, 3H).

[0294] Step 5:

[0295] To a solution of Compound 15e (200 mg, 615.71 μmol, equiv) in dichloromethane (5 mL) was added m-CPBA (265.63 mg, 1.23 mmol, purity: 80%, 2 equiv). The reaction mixture was stirred at 25 °C for 0.5 h. The reaction was quenched with saturated aqueous sodium sulfite solution (10 mL), then extracted with dichloromethane (20 mL). The organic layer was washed with saturated aqueous sodium carbonate solution (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to give Compound 15f. LCMS (ESI) m / z: 357.2 (M+1).

[0296] Step 6:

[0297] To a solution of Compound 15f (210 mg, 588.52 μmol, 1 equiv) and Compound 1e (314.72 mg, 1.47 mmol, 2.49 equiv, hydrochloride) in DMSO (3 mL) was added DIPEA (304.25 mg, 2.35 mmol, 410.04 μL, 4 equiv). The resulting reaction mixture was heated to 110 °C and stirred for 4 h. The reaction mixture was diluted with ethyl acetate (20 mL), then washed successively with water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The residue was separated and purified by preparative HPLC (column model: Waters Xbridge 150*25mm*5μm; mobile phase A: water containing 0.05% ammonia; mobile phase B: acetonitrile; gradient elution: 32% - 62%, 10 min) to give Compound 15. LCMS (ESI) m / z: 453.4 (M+1);1 1H NMR (400 MHz, DMSO-d6) δ 9.13 - 8.87 (m, 1H), 7.99 - 7.60 (m, 1H), 6.98 - 6.81 (m, 1H), 6.74 - 6.62 (m, 1H), 5.02 - 4.82 (m, 1H), 4.30 - 4.14 (m, 1H), 4.06 - 3.93 (m, 1H), 3.69 - 3.54 (m, 2H), 3.00 - 2.85 (m, 5H), 2.32 - 2.16 (m, 1H), 2.14 - 1.96 (m, 2H), 1.86 - 1.41 (m, 7H), 1.25 - 1.12 (m, 3H).

[0298] Example 14: Preparation of Compound 16 and Compound 17

[0299]

[0300] The first step:

[0301] To a 30 mL acetonitrile solution of 11k (3.2 g, 6.33 mmol, 1 eq) was added N-chlorosuccinimide (1.01 g, 7.59 mmol, 1.2 eq). The reaction mixture was heated to 60 °C and reacted for 12 h. After cooling to room temperature, the reaction mixture was quenched with 10 mL of saturated aqueous sodium sulfite solution, and the aqueous phase was extracted with 10 mL of dichloromethane three times. The combined organic phases were washed twice with 10 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product 16a was obtained. MS [ESI, M+1]: 540.2.

[0302] The second step:

[0303] To a solution of compound 16a (4 g, 7.40 mmol, 1 equiv) in 40 mL of tetrahydrofuran was added hydrochloric acid solution (1 mol / L, 40 mL, 5.40 equiv), and the resulting mixture was stirred at 25 °C for 1 h. The reaction solution was adjusted to pH 7 with saturated aqueous sodium bicarbonate, then extracted three times with 50 mL of ethyl acetate. The combined organic phases were washed twice with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The obtained crude product was purified by preparative HPLC (column model: Phenomenex luna C18 (250*70 mm, 15 μm); mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient elution 30%-60%, 20 min), and the obtained racemate was separated and purified by SFC (column model: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase A: carbon dioxide, mobile phase B: methanol containing 0.1% ammonia; gradient elution: mobile phase B / mobile phase A = 70%; flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; pressure: 100 Bar) to obtain compound 16 (retention time: 0.990 min) and compound 17 (retention time: 2.487 min).

[0304] The data characterization is as follows:

[0305] Compound 16 (retention time: 0.990 min): LCMS (ESI) m / z: 426.2; 1 1H NMR (400 MHz, CD3OD) δ = 9.05 (s, 1H), 7.56 (s, 1H), 4.71 - 4.60 (m, 1H), 4.21 - 4.05 (m, 2H), 3.80 - 3.72 (m, 2H), 3.09 - 2.98 (m, 2H), 2.92 - 2.87 (m, 3H), 2.29 - 2.18 (m, 3H), 2.18 - 2.08 (m, 1H), 2.03 - 1.84 (m, 3H), 1.83 - 1.63 (m, 3H).

[0306] Compound 17 (retention time: 2.487 min): LCMS (ESI) m / z: 426.2; 1 1H NMR (400 MHz, CD3OD) δ = 9.05 (s, 1H), 7.55 (s, 1H), 4.72 - 4.60 (m, 1H), 4.20 - 4.05 (m, 2H), 3.82 - 3.71 (m, 2H), 3.10 - 2.98 (m, 2H), 2.93 - 2.88 (m, 3H), 2.28 - 2.17 (m, 3H), 2.16 - 2.08 (m, 1H), 2.01 - 1.85 (m, 3H), 1.84 - 1.66 (m, 3H).

[0307] Example 15: Preparation of Compound 18

[0308]

[0309] First Step:

[0310] To a solution of Compound 14c (1.0 g, 3.82 mmol, 1.0 eq) in 1,2-dimethoxyethane (15 mL), add 18a (1,1,1-trifluoroisopropylamine (1.30 g, 8.67 mmol, 82.20 μL, 2.27 eq, hydrochloride)), sodium tert-butoxide (1.10 g, 11.46 mmol, 76.43 μL, 3 eq), (±)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (237.95 mg, 382.15 μmol, 0.1 eq) and bis(tri-tert-butylphosphine)palladium(0) (97.65 mg, 191.07 μmol, 0.05 eq). The mixture is heated to 85 °C under nitrogen protection and reacted for 10 hours. The reaction is cooled to room temperature, water (50 mL) is added, and the mixture is extracted with ethyl acetate (50 mL × 2). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness to obtain the crude product. The crude compound is purified by column chromatography (silica gel 100 - 200 mesh, petroleum ether / ethyl acetate = 15 / 1, 3 / 1) to obtain Compound 18b. 1 H NMR (400 MHz, CDCl3) δ = 9.13 (s, 1H), 7.26 (s, 1H), 6.71 - 6.40 (m, 2H), 5.31 - 5.18 (m, 1H), 2.69 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H); LCMS (ESI) m / z: 338.8 (m + 1) +

[0311] Second Step:

[0312] At 0 °C, to a solution of Compound 18b (1.1 g, 3.25 mmol, 1.0 eq) in dichloromethane (10 mL), add m-chloroperbenzoic acid (792.15 mg, 3.90 mmol, 85% purity, 1.2 eq). The mixture is reacted at 0 °C for 1 hour. The reaction solution is concentrated to dryness to obtain Compound 18c. LCMS (ESI) m / z: 354.9 (m + 1) +

[0313] Third Step:

[0314] To a solution of Compound 18c (5 mL) in dimethyl sulfoxide, N,N-diisopropylethylamine (1.56 g, 12.11 mmol, 2.11 mL, 5 equiv) and 4-amino-1-methylsulfonylpiperidine (1.04 g, 4.84 mmol, 2 equiv, hydrochloride) were added. The mixture was heated to 100 °C under nitrogen protection and reacted for 2 hours. The reaction was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (100-200 mesh silica gel, petroleum ether / ethyl acetate = 10 / 1, 5 / 1) to obtain Compound 18. 1 H NMR (400 MHz, CDCl3) δ = 8.97 (s, 1H), 7.19 (s, 1H), 6.74 - 6.36 (m, 2H), 5.51 - 5.34 (m, 1H), 4.42 - 4.27 (m, 2H), 4.19 - 4.02 (m, 1H), 3.90 - 3.72 (m, 2H), 3.08 - 2.93 (m, 2H), 2.86 (s, 3H), 2.31 - 2.17 (m, 2H), 1.75 (d, J = 9.8 Hz, 2H). LCMS (ESI) m / z: 468.9 (m + 1) +

[0315] Example 16: Preparation of Compound 19

[0316]

[0317] First step:

[0318] At 20 - 30 °C, to a solution of Compound 14c (120 mg, 458.58 μmol, 1 equiv) in dimethyl sulfoxide (4 mL), Compound 19a (152.91 mg, 138 μmol, 3 equiv) and diisopropylethylamine (177.80 mg, 138 μmol, 239.62 μL, 3 equiv) were added successively. The reaction solution was stirred at 100 °C for 12 hours under nitrogen protection. The reaction solution was quenched with water (15 mL), extracted twice with ethyl acetate (20 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:0 to 1:1) to obtain Compound 19b.

[0319] Second step:

[0320] At 0 °C, m-chloroperbenzoic acid (50.46 mg, 248.54 μmol, 85% purity, 1.1 eq) was added portionwise to a solution of compound 19b (76 mg, 225.95 μmol, 1 eq) in dichloromethane (2 mL). The reaction mixture was stirred at 0 °C for 1 h under nitrogen protection. At 0 - 5 °C, a saturated Na2SO3 (10 mL) solution was slowly added to the reaction mixture, and the mixture was stirred at 15 - 25 °C for 0.5 h to quench the reaction. The reaction mixture was extracted with dichloromethane (10 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product of compound 19c.

[0321] Step 3:

[0322] At 20 - 30 °C, compound 1e (97.50 mg, 454.08 μmol, 2 eq, hydrochloride) and diisopropylethylamine (117.37 mg, 908.16 μmol, 158.18 μL, 4 eq) were successively added to a solution of compound 19c (80 mg, 227.04 μmol, 1 eq) in dimethyl sulfoxide (3 mL). The reaction mixture was stirred at 100 °C for 6 h under nitrogen protection. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue.

[0323] The residue was purified by preparative HPLC (column model: YMC Triart 30*150mm*7μm; mobile phase: [water (hydrochloric acid) - acetonitrile]; 40% - 60%, 9 min) and (column model: Welch Ultimate XB - SiOH 250*50*10μm; mobile phase: n - heptane - ethanol (0.1% ammonia water); 15% - 55%, 15 min) to obtain compound 19. LCMS (ESI) m / z: 467.1 (M + 1) + , 1 1H NMR (400 MHz, DMSO - d6): δ = 9.14 (s, 1H), 8.80 (s, 1H), 7.96 - 7.89 (m, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 6.70 (t, J = 55.6 Hz, 1H), 4.41 - 4.28 (m, 1H), 3.75 (s, 3H), 3.59 - 3.55 (m, 2H), 2.99 - 2.93 (m, 2H), 2.88 (s, 3H), 2.04 - 2.00 (m, 2H), 1.84 (s, 3H), 1.64 - 1.55 (m, 2H).

[0324] Example 17: Preparation of Compound 20

[0325]

[0326] The first step

[0327] Under nitrogen protection, 14c (1 g, 3.82 mmol, 1 equiv), 20a (1.01 g, 7.64 mmol, 2 equiv), sodium tert-butoxide (1.10 g, 11.46 mmol, 3 equiv) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine; methanesulfonate; [2-[2-(methylamino)phenyl]phenyl]palladium (164.41 mg, 191.07 μmol, 0.05 equiv) were added to 1,4-dioxane (15 mL). Then the mixture was heated to 100 °C and stirred for 1 h. After cooling, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to give product 20b.

[0328] The second step

[0329] At 25 °C, m-chloroperbenzoic acid (682.83 mg, 3.36 mmol, 85% purity, 1.2 equiv) was added to a solution of 20b (1 g, 2.80 mmol, 1 equiv) in dichloromethane (15 mL). After addition, the mixture was stirred for 1 h. The mixture was quenched with aqueous sodium sulfite solution (20 mL) and stirred for 5 min, then extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give product 20c.

[0330] The third step

[0331] At 25 °C, diisopropylethylamine (624.06 mg, 4.83 mmol, 841.05 μL, 3 equiv) and 1e (691.17 mg, 3.22 mmol, 2 equiv, hydrochloride) were added to a solution of 20c (600 mg, 1.61 mmol, 1 equiv) in dimethyl sulfoxide (6 mL). Then the mixture was heated to 100 °C and stirred for 1 h. The mixture was diluted with aqueous solution (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (HCl)-ACN]; ACN%: 37%-57%, 7 min) to give 20. LCMS (ESI) m / z: 486.9 (M+1) 11H NMR (400 MHz, DMSO-d6) δ = 9.16 (s, 1H), 8.96 (s, 1H), 8.05 - 7.85 (m, 2H), 7.29 (s, 1H), 6.66 (t, J = 55.6 Hz, 1H), 4.34 (d, J = 2.4 Hz, 1H), 3.82 (s, 3H), 3.62 - 3.56 (m, 2H), 3.02 - 2.83 (m, 5H), 2.09 - 1.94 (m, 2H), 1.68 - 1.48 (m, 2H).

[0332] Example 18: Preparation of Compounds 21 and 22

[0333]

[0334] First Step:

[0335] At 20 - 30 °C, to a solution of Compound 14e (2.4 g, 9.17 mmol, 1 equiv) in N-methylpyrrolidone (24 mL) were successively added Compound 21a (3.32 g, 21.09 mmol, 2.3 equiv, hydrochloride) and diisopropylethylamine (5.45 g, 42.19 mmol, 7.35 mL, 4.6 equiv). The reaction mixture was reacted at 150 °C for 3 hours under microwave conditions. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (40 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain Compound 21b (

[0336] Second Step:

[0337] At 0 °C, m-chloroperbenzoic acid (1.23 g, 6.03 mmol, 85% purity, 1.1 equiv) was added portionwise to a solution of Compound 21b (1.9 g, 5.49 mmol, 1 equiv) in dichloromethane (20 mL). The reaction mixture was reacted at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude product of Compound 21c.

[0338] Third Step:

[0339] At 20 - 30 °C, to a solution of compound 21c (1.33 g, 3.67 mmol, 1 eq) in dimethyl sulfoxide (10 mL) were successively added compound 1e (1.58 g, 7.34 mmol, 2 eq) and diisopropylethylamine (1.90 g, 14.68 mmol, 2.56 mL, 4 eq). The reaction mixture was stirred at 100 °C for 6 h under nitrogen protection. The reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:0 to 2:1) and resolved by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃·H₂O in MeOH]; B%: 30% - 30%, 6.1 min; 120 min) to obtain compound 21 and compound 22. Compound 22 was purified by HPLC (column model: 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [water (0.05% hydrochloric acid) - acetonitrile]; 48% - 68%, 6.5 min).

[0340] Compound 21, LCMS (ESI) m / z: 477.1 (M + 1) + , 1 ¹H NMR (400 MHz, methanol - d₄): δ = 9.01 (s, 1H), 7.13 (s, 1H), 6.53 (t, J = 55.6 Hz, 1H), 4.83 - 4.79 (m, 1H), 4.14 - 4.07 (m, 1H), 3.76 - 3.71 (m, 2H), 3.06 - 3.01 (m, 2H), 2.88 (s, 3H), 2.42 - 2.16 (m, 6H), 1.92 - 1.85 (m, 2H), 1.73 - 1.69 (m, 2H).

[0341] Compound 22, LCMS (ESI) m / z: 477.2 (M + 1) + , 1 ¹H NMR (400 MHz, methanol - d₄): δ = 9.03 (s, 1H), 7.19 (s, 1H), 6.59 (t, J = 55.6 Hz, 1H), 4.92 - 4.87 (m, 1H), 4.16 - 4.07 (m, 1H), 3.77 - 3.72 (m, 2H), 3.03 - 2.97 (m, 2H), 2.88 (s, 3H), 2.41 - 2.14 (m, 6H), 1.93 - 1.86 (m, 2H), 1.75 - 1.70 (m, 2H).

[0342] Example 19: Preparation of Compounds 23 and 24

[0343]

[0344] First Step:

[0345] At 20 - 30 °C, to a solution of Compound 19c (100 mg, 275.98 μmol, 1 equiv) in dimethyl sulfoxide (3 mL) were successively added Compound 23a (118.29 mg, 551.96 μmol, 2 equiv) and DIEA (107.01 mg, 827.94 μmol, 144.21 μL, 3 equiv). The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. The reaction mixture was quenched with water (5 mL) and extracted twice with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel plate (eluent: petroleum ether:ethyl acetate = 3:1) to obtain Compound 23b. LCMS (ESI) m / z: 513.0 (M+1) + 。

[0346] Second Step:

[0347] At 0 °C, trifluoroacetic acid (266.95 mg, 2.34 mmol, 173.35 μL, 20 equiv) was added dropwise to a solution of Compound 23b (60 mg, 117.06 μmol, 1 equiv) in dichloromethane (2 mL). The reaction mixture was reacted at 0 °C for 0.5 h under nitrogen protection. The reaction mixture was concentrated to obtain Compound 23c. LCMS (ESI) m / z: 413.2 (M+1) + 。

[0348] Third Step:

[0349] At 0 °C, triethylamine (33.12 mg, 327.33 μmol, 45.56 μL, 3 equiv) and methanesulfonyl chloride (18.75 mg, 163.67 μmol, 12.67 μL, 1.5 equiv) were added to a solution of compound 23c (45 mg, 109.11 μmol, 1 equiv) in dichloromethane (2 mL). The reaction mixture was stirred at 0 °C under nitrogen for 0.5 h. The reaction was quenched with water (10 mL), and the mixture was extracted with dichloromethane (10 mL) three times. The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Unisil 3-100C18 Ultra 150*50mm*3μm; mobile phase: [water (formic acid)-acetonitrile]; 42%-72%, 10 min) to afford compound 23d. LCMS (ESI) m / z: 491.1 (M+1) + 。

[0350] Step 4:

[0351] Compound 23d was resolved by SFC (column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia ethanol]; 20%-20%, 4.8 min; 40min) to give compound 23 and compound 24.

[0352] Compound 23: LCMS (ESI) m / z: 491.2 (M+1) + 。 1 H NMR (METHANOL-d4, 400 MHz) δ9.04 (s, 1H), 7.16 (s, 1H), 6.56 (t, J = 56.0 Hz, 1H), 4.61 (br s, 1H), 4.36 (br s, 1H), 3.52 - 3.42 (m, 1H), 3.30 - 3.22 (m, 2H), 2.89 (s, 3H), 2.42 - 2.37 (m, 2H), 2.28 - 2.11 (m, 2H), 2.09 - 2.03 (m, 2H), 1.95 - 1.89 (m, 2H), 1.74 - 1.69 (m, 1H), 1.30 - 1.33 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H).

[0353] Compound 24: LCMS (ESI) m / z: 491.2 (M+1) + 。 11H NMR (methanol-d4, 400 MHz) δ 8.91 (s, 1H), 7.04 (s, 1H), 6.44 (t, J = 56.0 Hz, 1H), 4.49 (br s, 1H), 4.29 - 4.21 (m, 1H), 3.37 (td, J = 3.4, 11.4 Hz, 1H), 3.07 - 3.15 (m, 2H), 2.77 (s, 3H), 2.35 - 2.25 (m, 2H), 2.19 - 2.05 (m, 2H), 1.98 - 1.95 (m, 1H), 1.91 - 1.88 (m, 1H), 1.86 - 1.82 (m, 2H), 1.65 - 1.58 (m, 1H), 1.19 - 1.16 (m, 1H), 0.94 (d, J = 7.0 Hz, 3H).

[0354] Example 20: Preparation of Compound 25

[0355]

[0356] First Step

[0357] At room temperature, dissolve Compound 14c (80 mg, 305.72 μmol, 1 equiv), (2R)-2-methylpyrrole (25a) (65.08 mg, 764.30 μmol, 2.5 equiv), and N,N-diisopropylethylamine (197.56 mg, 1.53 mmol, 266.25 μL, 5 equiv) in dimethyl sulfoxide (2 mL). Carry out microwave reaction at 150 °C for 3 hours. Detect the completion of the reaction by LCMS. Add 5 mL of water to the reaction solution, and then extract three times with ethyl acetate (10 mL × 3). Wash the combined organic phases three times with saturated brine (10 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. Purify the crude product by thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 3 / 1) to obtain Compound 25b.

[0358] Second Step

[0359] At 0 °C, add m-chloroperoxybenzoic acid (69.64 mg, 343.01 μmol, 85% purity, 1.2 equiv) to a solution of Compound 25b (90 mg, 285.84 μmol, 98.571% purity, 1 equiv) in dichloromethane (5 mL), and react at 0 °C for 1 hour. Detect the completion of the reaction by LCMS. Quench the reaction solution with saturated sodium sulfite (5 mL) at 0 °C, dilute with 5 mL of water, and then extract three times with dichloromethane (10 mL × 3). Wash the combined organic phases twice with saturated aqueous sodium bicarbonate (15 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product Compound 25c.

[0360] Third Step

[0361] At room temperature, N,N-diisopropylethylamine (178.20 mg, 1.38 mmol, 240.17 μL, 3 eq) and compound 1e (148.03 mg, 689.41 μmol, 1.5 eq) were added to a solution of compound 25c (150 mg, 459.61 μmol, 1 eq) in dimethyl sulfoxide (5 mL), and the mixture was stirred at 100 °C for 4 h. The reaction was monitored by LCMS and found to be complete. 5 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column model: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [Heptane-EtOH]; B%: 15% - 55%, 15 min) to obtain compound 25. LCMS (ESI) m / z: 441.3 (M+1) 1 1H NMR (400 MHz, DMSO-d6) δ = 9.08 (s, 1H), 7.72 (s, 1H), 7.09 (s, 1H), 6.71 (t, J = 56.0 Hz, 1H), 5.00 - 4.87 (m, 1H), 4.17 - 4.04 (m, 1H), 3.98 - 3.82 (m, 2H), 3.64 - 3.54 (m, 2H), 3.47 - 3.40 (m, 2H), 2.95 - 2.85 (m, 4H), 2.14 - 2.07 (m, 1H), 2.07 - 1.95 (m, 3H), 1.93 - 1.81 (m, 1H), 1.74 - 1.54 (m, 2H), 1.23 (d, J = 6.13 Hz, 3H).

[0362] Example 21: Preparation of Compound 26

[0363]

[0364] The first step

[0365] At 25 °C, tert-butyl hydroperoxide (364.93 mg, 2.83 mmol, 388.23 μL, 70% purity, 6 eq) was added gradually to a solution of compound 1a (100 mg, 472.43 μmol, 1 eq) and sodium trifluoromethanesulfinate (368.64 mg, 2.36 mmol, 368.64 μL, 5 eq) in DMSO (4 mL). The reaction mixture was stirred at 25 °C for 15 h. The reaction was quenched with 10 mL of disodium ethylenediaminetetraacetate / NaHCO₃ solution and 5 mL of water, then diluted with 10 mL of ethyl acetate, and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by pre-TLC (eluent: petroleum ether:ethyl acetate = 5:1) to give compound 26a, MS (M + 1): 280.2.

[0366] The second step

[0367] To a solution of compound 26a (40 mg, 143.03 μmol, 1 eq) and 1b in DMSO (1.5 mL) was added DIEA (36.97 mg, 286.05 μmol, 49.82 μL, 2 eq). The reaction mixture was stirred at 120 °C for 12 h. The reaction was diluted with ethyl acetate (6 mL) and poured into 10 mL of water at room temperature, and extracted with ethyl acetate (6 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to give compound 26b, MS (M + 1): 359.3.

[0368] The third step

[0369] At 25 °C, a compound of potassium monopersulfate with potassium sulfate and potassium bisulfate (102.92 mg, 167.42 μmol, 2 eq) was added to a solution of compound 26b (30 mg, 83.71 μmol, 1 eq) in THF (3 mL) and H₂O (1 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched with 6 mL of saturated sodium sulfite, and extracted with ethyl acetate (6 mL × 3). The combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product 26c was used directly in the next step without further purification. MS (M + 1): 375.2.

[0370] The fourth step

[0371] To a solution of compound 26c (32 mg, 85.47 μmol, 1 equiv) in DMSO (1.5 mL) were successively added DIEA (33.14 mg, 256.42 μmol, 44.66 μL, 3 equiv) and 1e (22.85 mg, 128.21 μmol, 1.5 equiv). The reaction mixture was stirred at 100 °C for 2 h. The reaction was poured into water (10 mL) at room temperature. The reaction mixture was diluted with ethyl acetate (6 mL), and extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The residue was purified by HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 41%-71%, 10 min) to afford compound 26. MS (M+1): 489.4. 1 H NMR (400 MHz, METHANOL-d4) δ=9.02 (s, 1H), 7.27 (s, 1H), 4.30 - 4.09 (m, 2H), 3.74 (d, J=12.2 Hz, 2H), 3.01 (t, J=11.0 Hz, 2H), 2.88 (s, 3H), 2.41 - 2.26 (m, 1H), 2.17 (d, J=11.4 Hz, 2H), 1.96 - 1.64 (m, 7H), 1.18 (s, 3H).

[0372] Example 22: Preparation of Compound 27

[0373]

[0374] The First Step

[0375] To a solution of compound 2b (10 g, 34.42 mmol, 1 equiv) in THF (50 mL) and methanol (50 mL) was added sodium methoxide (2.42 g, 44.74 mmol, 1.3 equiv). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was filtered, and the filter cake was washed with water (10 mL × 5) and methanol (10 mL × 5). The filter cake was dried in vacuo to give compound 27a.

[0376] The Second Step

[0377] Under a nitrogen atmosphere, cesium carbonate (22.77 g, 69.89 mmol, 2 eq), tris(dibenzylideneacetone)dipalladium(0) (1.60 g, 1.75 mmol, 0.05 eq), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.02 g, 3.49 mmol, 0.1 eq) were added to a solution of compound 27a (10 g, 34.95 mmol, 1 eq) and tert-butyl carbamate (6.55 g, 55.92 mmol, 1.6 eq) in 1,4-dioxane (200 mL). The reaction mixture was purged with N2 gas three times and then reacted at 100 °C for 16 h. After the reaction, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (30 mL × 3). Then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound 27b. MS (M+1): 323.0.

[0378] The third step

[0379] To a solution of compound 27b (4 g, 12.41 mmol, 1 eq) in 1,4-dioxane (30 mL) was added 300 mL of water, and the reaction mixture was reacted at 110 °C for 48 h. After the reaction was completed, the reaction mixture was filtered, and the filter cake was dried in vacuo to obtain the product. The filtrate was extracted with ethyl acetate (200 mL × 2), the combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain product 27c. MS (M+1): 222.8.

[0380] The fourth step

[0381] Under nitrogen protection, lithium tetrafluoroborate (2.28 g, 24.30 mmol) was added in one portion to a suspension of 27c (0.27 g, 1.21 mmol) in acetonitrile (5 mL). The mixture was cooled to an external temperature of 0 - 5 °C, tert-butyl nitrite (0.15 g, 1.46 mmol) was added, and the mixture was stirred for 5 min. Then anhydrous toluene (30 mL) was added, and the mixture was heated to an external temperature of 120 °C and stirred for 2 h. The reaction mixture was concentrated and separated by preparative TLC plate (petroleum ether:ethyl acetate 8:1 (v / v)) to obtain 27d (81 mg, 0.3 mmol). LCMS (ESI) m / z: 226.10 (M+1).

[0382] The fifth step

[0383] Under nitrogen protection, hydrobromic acid / acetic acid solution (2 mL, 33%) was added to 27d (81 mg, 0.3 mmol), and the mixture was stirred at 50 °C for 2 h. The mixture was concentrated to obtain the crude product 27e.

[0384] The sixth step

[0385] Under nitrogen protection, phosphorus oxychloride (373 mg, 1.3 mmol) was added to a solution of 27e (55 mg, 260 μmol) in acetonitrile (1 mL), and the reaction was stirred at 75 °C for 1 hour. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by a preparative plate (petroleum ether: ethyl acetate 8:1 (v / v)) to obtain 27f.

[0386] The seventh step

[0387] Under nitrogen protection, Pd2(dba)3 (5 mg, 5.4 μmol), t-Bu Xphos (4.9 mg, 12 μmol) and sodium tert-butoxide (11.2 mg, 120 μmol) were added to a solution of 27f (16 mg, 58 μmol) and 1b (6.7 mg, 58 μmol) in dioxane (1 mL). The reaction was stirred at 90 °C for 2 hours. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by a preparative plate (petroleum ether: ethyl acetate 3:1 (v / v)) to obtain 27g.

[0388] The eighth step

[0389] m-Chloroperoxybenzoic acid (19.7 mg, 97 μmol, 85%) was added to a solution of 27g (15 mg, 48.6 μmol) in dichloromethane (1 mL), and the reaction was stirred at 30 °C for 2 hours. The reaction solution was directly separated by a preparative separation plate (EtOAc) to obtain 27h. LCMS (ESI) m / z: 341.1 (M+1).

[0390] The ninth step

[0391] Under nitrogen protection, 27h (8 mg, 23 μmol) and 1e (5.6 mg, 26 μmol) were dissolved in DMSO (0.5 mL), and diisopropylethylamine (6 mg, 46 μmol) was added. The reaction was stirred at 105 °C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with ethyl acetate (50 mL), washed with water (20 mL × 2), washed with saturated brine (20 mL), dried over sodium sulfate, filtered, concentrated, and the residue was separated by preparative TLC (EtOAc) to obtain 27. LCMS (ESI) m / z: 439.18 (M+1). 11H NMR (400 MHz, CDCl3) δ = 9.07 (s, 1H), 7.46 (s, 1H), 4.03 (br, 2H), 3.73 (d, J = 13.2 Hz, 2H), 2.99 - 2.94 (m, 2H), 2.92 (s, 3H), 2.18 - 2.15 (m, 4H), 1.80 - 1.65 (m, 6H), 1.06 (s, 3H).

[0392] Example 23: Preparation of Compounds 28 and 29

[0393]

[0394] First Step:

[0395] At 20 - 30 °C, to a solution of Compound 19c (30 mg, 82.79 μmol, 1 equiv) in dimethyl sulfoxide (1 mL) was added Compound 28a (34.65 mg, 165.59 μmol, 2 equiv) and DIEA (32.10 mg, 248.38 μmol, 43.26 μL, 3 equiv). The reaction mixture was stirred at 100 °C for 12 h under nitrogen protection. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL) three times. The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by preparative HPLC (column model: Phenomenex C18 75*30mm*3μm; mobile phase: [water (formic acid) - acetonitrile]; 38% - 68%, 7 min) to afford Compound 28b.

[0396] Second Step

[0397] Compound 28b was resolved by SFC (column model: DAICEL CHIRALPAK AD - H (250mm*30mm, 5μm); mobile phase: [0.1% ammonia in ethanol]; 30% - 30%, 3.5 min; 40 min) to obtain Compound 28 or 29. LCMS (ESI) m / z: 478.1 (M + 1)+. 1 1H NMR (METHANOL - d4, 400 MHz) δ 8.90 (s, 1H), 7.03 (s, 1H), 6.44 (t, J = 56 Hz, 1H), 4.51 (br s, 1H), 3.96 - 3.85 (m, 1H), 3.58 - 3.54 (m, 2H), 2.79 - 2.70 (m, 2H), 2.35 - 2.25 (m, 1H), 2.20 - 2.05 (m, 4H), 1.83 - 1.72 (m, 2H), 1.65 - 1.56 (m, 3H). Compound 28 or 29. LCMS (ESI) m / z: 478.1 (M + 1)+. 11H NMR (Methanol-d4, 400 MHz) δ 8.90 (s, 1H), 7.03 (s, 1H), 6.44 (t, J = 56.0 Hz, 1H), 4.51 (s, 1H), 3.95 - 3.85 (m, 1H), 3.60 - 3.55 (m, 2H), 2.79 - 2.71 (m, 2H), 2.35 - 2.26 (m, 1H), 2.20 - 2.03 (m, 4H), 1.86 - 1.72 (m, 2H), 1.69 - 1.53 (m, 3H).

[0398] Example 24: Preparation of Compounds 30 and 31

[0399]

[0400] First Step

[0401] At 0 °C, triethylamine (1.04 g, 10.24 mmol, 1.43 mL, 1.2 eq) and methanesulfonyl chloride (1.27 g, 9.39 mmol, 938.78 μL, 1.1 eq) were slowly added dropwise to a solution of compound 30a (2 g, 8.54 mmol, 1 eq) in dichloromethane (20 mL). The reaction mixture was stirred at 20 °C for 2 h. Compound 30b was obtained and the reaction mixture was directly used for the next step.

[0402] Second Step

[0403] At 0 °C, triethylamine (3.45 g, 34.13 mmol, 4.75 mL, 4 eq) and methylamine (2 M, 12.80 mL, 3 eq) were added to a solution of compound 30b (2.84 g, 8.53 mmol, 1 eq) in dichloromethane (20 mL). The reaction mixture was stirred at 20 °C for 13 h. After completion of the reaction, the reaction mixture was dispersed in a solution of 50 mL of water and 100 mL of dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by thin-layer chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to obtain compound 30c. 1 1H NMR (400 MHz, Chloroform-d) δ = 7.34 - 7.22 (m, 5H), 5.10 - 4.93 (m, 2H), 4.76 - 4.57 (m, 1H), 4.12 - 3.93 (m, 1H), 3.69 - 3.46 (m, 3H), 2.97 - 2.76 (m, 2H), 2.06 - 1.86 (m, 2H), 1.50 - 1.35 (m, 2H).

[0404] Third Step

[0405] At room temperature, under nitrogen protection, palladium on carbon (0.2 g, 1.22 mmol, 10% purity) was added to a solution of compound 30c (0.6 g, 1.83 mmol, 1 equiv) in tetrahydrofuran (5 mL). The solution was purged with hydrogen several times and reacted at 20 °C under hydrogen protection (15 psi) for 16 h. After completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated to obtain compound 30d. 1 H NMR (400 MHz, DMSO-d6) δ = 7.08 - 6.90 (m, 1H), 3.54 - 3.37 (m, 1H), 3.41 (td, J = 3.3, 12.4 Hz, 3H), 2.78 - 2.59 (m, 3H), 2.50 (br s, 3H), 1.85 - 1.64 (m, 2H), 1.32 - 1.14 (m, 2H).

[0406] The fourth step

[0407] To a solution of compound 30d (90 mg, 146.05 μmol, 58.8% purity, 1 equiv) in dimethyl sulfoxide (2 mL) were added N,N-diisopropylethylamine (56.63 mg, 438.15 μmol, 76.32 μL, 3 equiv) and compound 19c (42.34 mg, 219.07 μmol, 1.5 equiv). The reaction mixture was stirred at 100 °C for 3 h. The reaction was quenched with 10 mL of water and extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (column model: Phenomenex Gemini-NXC18 75*30 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; ACN%: 40% - 70%, 7 min) to obtain compound 30e.

[0408] The fifth step

[0409] 30e was resolved by SFC (column model: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O MEOH]; B%: 30% - 30%, 3.8 min; 30 min) to obtain compound 30 and compound 31.

[0410] Compound 30: LCMS (ESI) m / z: 491.17 (M + 1) 11H NMR (400 MHz, DMSO-d6) δ = 9.29 - 9.04 (m, 1H), 8.09 - 7.89 (m, 1H), 7.29 - 7.15 (m, 1H), 7.13 - 7.04 (m, 1H), 6.92 - 6.73 (m, 2H), 6.64 - 6.61 (m, 1H), 4.97 - 4.71 (m, 1H), 4.08 - 3.91 (m, 1H), 3.59 - 3.48 (m, 3H), 3.02 - 2.76 (m, 2H), 2.32 - 2.14 (m, 3H), 2.05 - 1.90 (m, 2H), 1.90 - 1.73 (m, 3H), 1.70 - 1.50 (m, 3H).

[0411] Compound 31: LCMS (ESI) m / z: 491.17 (M+1) 1 1H NMR (400 MHz, DMSO-d6) δ = 9.32 - 9.01 (m, 1H), 8.09 - 7.86 (m, 1H), 7.24 - 7.19 (m, 1H), 7.14 - 7.05 (m, 1H), 6.93 - 6.61 (m, 2H), 6.95 - 6.56 (m, 1H), 4.90 - 4.73 (m, 1H), 4.07 - 3.96 (m, 1H), 3.57 - 3.48 (m, 3H), 2.95 - 2.83 (m, 2H), 2.32 - 2.16 (m, 3H), 2.06 - 1.92 (m, 2H), 1.88 - 1.73 (m, 3H), 1.68 - 1.52 (m, 3H).

[0412] Example 25: Preparation of Compound 32

[0413]

[0414] The first step

[0415] 3 g of 19c was resolved by SFC (column model: Phenomenex luna C18 250*80 mm*10 μm; mobile; mobile phase: [water (0.1% TFA) - ACN]; ACN%: 60% - 90%, 21 min to obtain Compound 32a (retention time: 1.150 min) and 32b (retention time: 1.259 min).

[0416]

[0417] The second step

[0418] At 0 °C, m-chloroperoxybenzoic acid (25.79 mg, 127.04 μmol, 85% purity, 1.1 eq) was added to a solution of compound 32a (40 mg, 115.49 μmol, 1 eq) in dichloromethane (5 mL), and the mixture was stirred at this temperature for 30 minutes. After the reaction was complete, it was quenched with saturated sodium sulfite (5 mL) at 0 °C, diluted with 5 mL of water, and then extracted three times with dichloromethane (10 mL × 3). The combined organic phases were washed twice with saturated aqueous sodium bicarbonate (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 32c.

[0419] The third step

[0420] At room temperature, N,N-diisopropylethylamine (99.87 mg, 772.74 μmol, 134.60 μL, 4 eq) and compound 32d (83.56 mg, 386.37 μmol, 2 eq) were added to a solution of compound 32c (70 mg, 193.19 μmol, 1 eq) in dimethyl sulfoxide (5 mL). The mixture was stirred at 100 °C for 16 hours. After the reaction was complete, 10 mL of water was added to the reaction solution, and it was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate = 1:1) to obtain compound 32e.

[0421] The fourth step

[0422] At 0 °C, trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 138.98 eq) was added to a solution of compound 32e (50 mg, 97.18 μmol, 1 eq) in dichloromethane (2 mL), and the mixture was stirred at this temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated to obtain the crude product 32f.

[0423] The fifth step

[0424] At 0 °C, sodium bicarbonate (36.49 mg, 434.36 μmol, 16.89 μL, 3 eq) and methanesulfonyl chloride (49.76 mg, 434.36 μmol, 33.62 μL, 2 eq) were added to a solution of compound 32f (60 mg, 144.79 μmol, 1 eq) in water (1 mL) and ethyl acetate (1 mL). The reaction mixture was stirred at this temperature for 1 h. Since the reaction was not complete, the temperature was raised to 20 °C and stirred for 12 h. After the reaction was complete, 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (10 mL × 3). The combined organic phases were washed three times with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative-HPLC (column model: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (FA)-ACN]; ACN%: 35% - 65%, 7 min) to obtain compound 32. LCMS (ESI) m / z: 492.16 1 1H NMR (400 MHz, DMSO-d6) δ = 9.31 - 9.05 (m, 1H), 7.64 - 7.14 (m, 2H), 7.11 - 6.56 (m, 2H), 5.31 - 5.16 (m, 1H), 4.92 - 4.76 (m, 1H), 4.25 - 4.12 (m, 1H), 4.10 - 4.00 (m, 1H), 3.77 - 3.62 (m, 2H), 3.18 - 2.98 (m, 2H), 2.94 (s, 3H), 2.29 - 2.20 (m, 3H), 2.05 - 1.87 (m, 1H), 1.88 - 1.68 (m, 4H).

[0425] Example 26: Preparation of Compounds 33 and 34

[0426]

[0427] The First Step

[0428] At -78 °C, methyllithium reagent (3 mol / L, 41.41 mL, 2 eq) was slowly added dropwise to a solution of compound 33a (10 g, 62.11 mmol, 1 eq) in tetrahydrofuran (20 mL). The reaction mixture was stirred at -78 °C for 0.5 h under nitrogen protection. The reaction was quenched by pouring the reaction mixture into saturated ammonium chloride solution (100 mL), and the mixture was extracted twice with ethyl acetate (150 mL). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:0 to 8:1) to obtain compound 33b (2.8 g, 15.82 mmol, 25.46% yield). 11H NMR (400 MHz, DMSO-d6): δ = 5.92 (t, J = 2.6 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.21 - 2.12 (m, 1H), 2.03 - 1.88 (m, 2H), 1.18 (s, 3H).

[0429] The second step

[0430] At -78 °C, a solution of tert-butyllithium reagent (1.3 M, 42.58 mL, 2 eq) was slowly added dropwise to a solution of compound 33b (2.8 g, 15.82 mmol, 1 eq) in tetrahydrofuran (60 mL). The reaction mixture was slowly warmed to -20 °C under nitrogen protection and stirred at -20 °C for 0.5 h. Then the reaction mixture was cooled to -78 °C, and compound 33c (7.36 g, 39.54 mmol, 8.07 mL, 2.5 eq) was slowly added dropwise to the reaction mixture. Subsequently, the reaction mixture was slowly warmed to -20 °C and stirred at -20 °C for 0.5 h. At -20 °C, acetic acid (3 mL) was slowly added dropwise to quench the reaction. Then 80 mL of water was added to dilute the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound 33d (6.6 g).

[0431] The third step

[0432] At 20 - 30 °C, compound 14c (1.07 g, 4.78 mmol, 2.5 eq), bis(tri-tert-butylphosphine)palladium (48.82 mg, 95.54 μmol, 0.05 eq), and potassium phosphate (1.22 g, 5.73 mmol, 3 eq) were successively added to a mixed solution of compound 33d (0.5 g, 1.91 mmol, 1 eq) in dioxane (10 mL) and water (2 mL). The reaction mixture was stirred at 90 °C for 1 h under nitrogen protection. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 33e (0.36 g, 1.11 mmol, 58.27% yield). 11H NMR (400 MHz, DMSO-d6): δ = 9.61 (s, 1H), 8.17 (s, 1H), 7.66 (t, J = 2.8 Hz, 1H), 7.37 - 7.09 (m, 1H), 5.12 (s, 1H), 2.65 (s, 3H), 2.64 - 2.59 (m, 1H), 2.56 - 2.52 (m, 1H), 2.06 - 2.00 (m, 2H), 1.52 (s, 3H).

[0433] The fourth step

[0434] At 0 °C, m-chloroperoxybenzoic acid (248.62 mg, 1.22 mmol, 85% purity, 1.1 eq) was added portionwise to a solution of compound 33e (0.36 g, 1.11 mmol, 1 eq) in dichloromethane (10 mL). The reaction mixture was stirred at 0 °C for 1 h under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain the crude product of compound 33f (0.378 g).

[0435] The fifth step

[0436] At 20 - 30 °C, compound 1e (478.32 mg, 2.23 mmol, 2 eq, hydrochloride) and diisopropylethylamine (575.84 mg, 4.46 mmol, 776.06 μL, 4 eq) were successively added to a solution of compound 33f (0.378 g, 1.11 mmol, 1 eq) in dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 100 °C for 5 h under nitrogen protection. The reaction mixture was diluted with water (15 mL), extracted with ethyl acetate (15 mL × 2), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:0 to 1:2) to obtain compound 33g (0.2 g, 441.01 μmol, 39.59% yield).

[0437] The sixth step

[0438] At 20 - 30 °C, tris(triphenylphosphine)rhodium(III) chloride (116.29 mg, 125.7 μmol, 0.3 eq) was added to a solution of compound 33g (190 mg, 418.96 μmol, 1 eq) in ethanol (10 mL). The reaction mixture was stirred at 50 °C for 0.5 h under a hydrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column model: Waters Xbridge 150*25mm*5μm; mobile phase: [ammonia - acetonitrile]; acetonitrile %: 27% - 57%, 9 min) to obtain compound 33 (retention time 2.072 min) and 34 (retention time 2.427 min).

[0439] Compound 33 was purified by preparative HPLC (column model: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile%: 9%-29%, 10 minutes). LCMS (ESI) m / z: 456.1(M+1)+, 1 1H NMR (400 MHz, DMSO-d6): δ = 8.21 (s, 1H), 7.20 (s, 1H), 6.74 (t, J = 56 Hz, 1H), 4.88 (m, 1H), 4.43 - 4.38 (m, 2H), 3.53 (m, 2H), 2.89 (s, 3H), 2.83 - 2.76 (m, 2H), 2.61 - 2.52 (m, 2H), 2.25 (m, 1H), 2.14 - 1.86 (m, 4H), 1.77 - 1.65 (m, 4H), 1.51 - 1.40 (m, 2H).

[0440] Compound 34 was purified by preparative HPLC (column model: Phenomenex Synergi C18 150*25mm*10μm; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile%: 36%-56%, 10 minutes). LCMS (ESI) m / z: 456.2(M+1)+, 1 1H NMR (400 MHz, DMSO-d6): δ = 9.34 (s, 1H), 8.13 (br d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.06 (t, J = 56 Hz, 1H), 4.88 (s, 1H), 4.10 - 3.98 (m, 2H), 3.58 - 3.55 (m, 2H), 2.97 - 2.90 (m, 5H), 2.09 - 2.05 (m, 2H), 1.93 - 1.61 (m, 8H), 1.25 (s, 3H).

[0441] Refer to the synthesis methods in the above examples to synthesize the compounds in the following table:

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448] Experimental Example 1: Enzyme Activity Test

[0449] Experimental materials:

[0450] CDK1 / CyclinB1 kinase, CDK2 / CyclinA2 kinase, CDK2 / CyclinE1 kinase, CDK4 / CyclinD1 kinase, CDK6 / CyclinD1 kinase, CDK7 / CyclinH / MAT1 kinase, CDK9 / CyclinT1 kinase, LANCE UltraULight TM -4E-BP-1(Thr37146) Peptide EU-ANTI-P-4EBP1(THR37 / 46), Nivo multi-label analyzer

[0451] Experimental methods:

[0452] ● CDK1 / CyclinB1 enzyme reaction system

[0453] Dilute the enzyme, substrate, adenosine triphosphate and inhibitor using the kinase buffer in the kit. Dilute the test compound 5-fold to the 8th concentration with a multi-channel pipette, i.e., from 50 μM to 0.65 nM, with a DMSO concentration of 5%, and set up a double-replicate experiment. Add 1 μL of each concentration gradient of the inhibitor, 2 μL of CDK1 / CyclinB1 enzyme (12.5 ng), and 2 μL of the mixture of substrate and ATP (25 μM adenosine triphosphate, 0.2 μg / μL substrate) to the microplate. At this time, the final concentration gradient of the compound is diluted from 10 μM to 0.13 nM. Place the reaction system at 25 °C for 120 minutes. After the reaction, add 5 μL of ADP-Glo reagent to each well and continue the reaction at 25 °C for 40 minutes. After the reaction ends, add 10 μL of the kinase detection reagent to each well and read the chemiluminescence using a multi-label analyzer after reacting at 25 °C for 30 minutes, with an integration time of 0.5 seconds.

[0454] ● CDK2 / CyclinA2 enzyme reaction system

[0455] Dilute the enzyme, substrate, adenosine triphosphate, and inhibitor using the kinase buffer in the kit. Dilute the compound to be tested 5-fold to the 8th concentration using a multi-channel pipette, i.e., from 50 μM to 0.65 nM, with a DMSO concentration of 5%, and set up a double-replicate experiment. Add 1 μL of each concentration gradient of the inhibitor, 2 μL of CDK2 / CyclinA2 enzyme (1.6 ng), and 2 μL of the mixture of substrate and ATP (50 μM adenosine triphosphate, 0.1 μg / μL substrate) to the microplate. At this time, the final concentration gradient of the compound is from 10 μM to 0.13 nM. Incubate the reaction system at 25 °C for 60 minutes. After the reaction, add 5 μL of ADP-Glo reagent to each well and continue the reaction at 25 °C for 40 minutes. After the reaction is completed, add 10 μL of the kinase detection reagent to each well and read the chemiluminescence using a multi-label analyzer after reacting at 25 °C for 30 minutes, with an integration time of 0.5 seconds.

[0456] ● CDK2 / CyclinE1 enzyme reaction system

[0457] Dilute the enzyme, substrate, adenosine triphosphate, and inhibitor using the kinase buffer in the kit. Dilute the compound to be tested 5-fold to the 8th concentration using a multi-channel pipette, i.e., from 50 μM to 0.65 nM, with a DMSO concentration of 5%, and set up a double-replicate experiment. Add 1 μL of each concentration gradient of the inhibitor, 2 μL of CDK2 / CyclinE1 enzyme (2 ng), and 2 μL of the mixture of substrate and ATP (150 μM adenosine triphosphate, 0.1 μg / μL substrate) to the microplate. At this time, the final concentration gradient of the compound is from 10 μM to 0.13 nM. Incubate the reaction system at 25 °C for 60 minutes. After the reaction, add 5 μL of ADP-Glo reagent to each well and continue the reaction at 25 °C for 40 minutes. After the reaction is completed, add 10 μL of the kinase detection reagent to each well and read the chemiluminescence using a multi-label analyzer after reacting at 25 °C for 30 minutes, with an integration time of 0.5 seconds.

[0458] ● CDK4 / CyclinD1 enzyme reaction system

[0459] Preparation of kinase buffer:

[0460] The components of the buffer include: 50 mM N-(2-hydroxyethyl)piperazine-N′-ethanesulfonic acid solution with a pH of 7.5, 1 mM ethylenediaminetetraacetic acid, 10 mM magnesium chloride, 0.01% Brij-35, and 2 mM dithiothreitol.

[0461] Dilute the enzyme, substrate LANCE Ultra ULight with the kinase buffer TM-4E-BP-1(Thr37146) Peptide, adenosine triphosphate, and inhibitor. The compound to be tested was serially diluted 5-fold to the 8th concentration using a multi-channel pipette, i.e., from 40 μM to 0.512 nM, with a DMSO concentration of 4%, and a double-replicate experiment was set up. Add 2.5 μL of each concentration gradient of the inhibitor and 5 μL of CDK4 / CyclinD1 enzyme (0.5 ng) to the microplate, incubate at 25 °C for 60 minutes, then add 2.5 μL of the mixture of substrate and ATP (350 μM adenosine triphosphate, 12.5 nM substrate). At this time, the final concentration gradient of the compound was diluted from 10 μM to 0.128 nM. The reaction system was incubated at 25 °C for 120 minutes. After the reaction, add 5 μL of EDTA and 2X LANCE TM Detection Buffer (1:1) mixture, incubate at 25 °C for 5 minutes. After the reaction, add 5 μL of LANCE Ultra Eu-anti-P-4E-BP1(Thr37MS) (4 nM) to each well, incubate at 25 °C for 60 minutes, and then detect the reaction signal using a Nivo instrument according to the principle of time-resolved fluorescence resonance energy transfer.

[0462] ● CDK6 / CyclinD1 enzyme reaction system

[0463] Preparation of kinase buffer:

[0464] The components of the buffer include: 50 mM N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid solution at pH 7.5, 1 mM ethylenediaminetetraacetic acid, 10 mM magnesium chloride, 0.01% Brij-35, and 2 mM dithiothreitol.

[0465] Dilute the enzyme and substrate LANCE Ultra ULight with kinase buffer TM -4E-BP-1(Thr37146) Peptide, adenosine triphosphate, and inhibitor.

[0466] The compound to be tested was serially diluted 5-fold to the 8th concentration using a multi-channel pipette, i.e., from 40 μM to 0.512 nM, with a DMSO concentration of 4%, and a double-replicate experiment was set up. Add 2.5 μL of each concentration gradient of the inhibitor and 5 μL of CDK6 / CyclinD1 enzyme (0.5 ng) to the microplate, incubate at 25 °C for 60 minutes, then add 2.5 μL of the mixture of substrate and ATP (250 μM adenosine triphosphate, 12.5 nM substrate). At this time, the final concentration gradient of the compound was diluted from 10 μM to 0.128 nM. The reaction system was incubated at 25 °C for 120 minutes. After the reaction, add 5 μL of EDTA and 2X LANCE TMDetection Buffer (1:1) mixture, react at 25 °C for 5 minutes. After the reaction is completed, add 5 μL of LANCE Ultra Eu-anti-P-4E-BP1 (Thr37MS) (4 nM) to each well, and react at 25 °C for 60 minutes. Then, according to the principle of time-resolved fluorescence resonance energy transfer, use a Nivo instrument to detect the reaction signal.

[0467] ● CDK7 / CyclinH / MAT1 enzyme reaction system

[0468] Dilute the enzyme, substrate (MBP), adenosine triphosphate, and inhibitor using the kinase buffer in the kit. Dilute the test compound 5-fold with a multi-channel pipette to the 8th concentration, i.e., from 50 μM to 0.65 nM, with a DMSO concentration of 5%, and set up a double-replicate experiment. Add 1 μL of each concentration gradient of the inhibitor, 2 μL of CDK7 / CyclinH / MAT1 enzyme (total 20 ng), and 2 μL of the mixture of substrate and ATP (10 μM adenosine triphosphate, 0.1 μg / μL substrate) to the microplate. At this time, the final concentration gradient of the compound is from 10 μM to 0.13 nM. Place the reaction system at 25 °C for 120 minutes. After the reaction is completed, add 5 μL of ADP-Glo reagent to each well, continue to react at 25 °C for 40 minutes. After the reaction is completed, add 10 μL of the kinase detection reagent to each well, and read the chemiluminescence using a multi-label analyzer after reacting at 25 °C for 30 minutes, with an integration time of 0.5 seconds.

[0469] ● CDK9 / CyclinT1 enzyme reaction system

[0470] Dilute the enzyme, substrate, adenosine triphosphate, and inhibitor using the kinase buffer in the kit. Dilute the test compound 5-fold with a multi-channel pipette to the 8th concentration, i.e., from 50 μM to 0.65 nM, with a DMSO concentration of 5%, and set up a double-replicate experiment. Add 1 μL of each concentration gradient of the inhibitor, 2 μL of CDK9 / CyclinT1 enzyme (4 ng), and 2 μL of the mixture of substrate and ATP (100 μM adenosine triphosphate, 0.2 μg / μL substrate) to the microplate. At this time, the final concentration gradient of the compound is from 10 μM to 0.13 nM. Place the reaction system at 25 °C for 120 minutes. After the reaction is completed, add 5 μL of ADP-Glo reagent to each well, continue to react at 25 °C for 40 minutes. After the reaction is completed, add 10 μL of the kinase detection reagent to each well, and read the chemiluminescence using a multi-label analyzer after reacting at 25 °C for 30 minutes, with an integration time of 0.5 seconds.

[0471] Data analysis:

[0472] Convert the raw data into the inhibition rate using the equation (Sample - Min) / (Max - Min)*100%, IC 50The value can be obtained by curve fitting with four parameters (derived from the log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the enzymatic inhibitory activities of the compounds of the present invention against CDK1 / CyclinB1, CDK2 / CyclinA2, CDK2 / CyclinE1, CDK4 / CyclinD1, CDK6 / CyclinD1, CDK7 / CyclinH / MAT1, and CDK9 / CyclinT1 enzymes.

[0473] Table 1 Test Results of Enzymatic Activity

[0474]

[0475] Note: " / " indicates not tested

[0476] Experimental Conclusion:

[0477] The compounds of the present invention have significant inhibitory activity against CDK2 kinase, certain inhibitory activity against CDK4 and CDK6 kinases, weak inhibitory activity against CDK1 kinase, and certain selectivity against CDK7 and CDK9 kinases.

[0478] Experimental Example 2: Cell Activity Test

[0479] Experimental Materials:

[0480] 1) Reagents and Consumables

[0481] Reagent Brand Article number Batch number RPIM1640 Medium ATCC 22400-089 2193294 Fetal bovine serum ExCell Bio FSP500 11I323 Double antibody (penicillin, streptomycin) HyClone SV30010 J200049 Phosphate buffer solution Corning 21031CVC 21031031 0.25% Trypsin Gibco 25200072 2185855 CellTiter Glo buffer Promega G756B 0000433295 CellTiter Glo substrate Promega G755B 0000440444 96-well plate Greiner 781091 E19113Q3

[0482] 2) Experimental Instruments

[0483] Instrument Manufacturer Model Biological safety cabinet AIRTECH BSC-1304IIA2 Carbon dioxide incubator Thermo 311 Cell counter BECKMAN Vi-cellXR Microplate reader PerkinElmer Envision

[0484] 3) Cell Information

[0485] Cell name Tumor type Cell type Medium Inoculation number of 384-well plate Source Article number OVCAR-3 Ovarian Cancer Adherent RPMI-1640 + 10% FBS 1000 ATCC HTB-161 MCF-7-PR Breast cancer Adherent RPMI-1640 + 10% FBS 1000 WuXi NA

[0486] Experimental Method:

[0487] 1) Cell Culture and Subculture

[0488] ⑴ The culture medium is shown in the following table

[0489] ⑵ The cells are separated and subcultured every 3 - 4 days

[0490] 2) On the first day: Seed the cell plate

[0491] ⑴ Preheat the phosphate buffer PBS, trypsin, and culture medium used in the cell subculture process in a 37°C water bath.

[0492] (2) Take out the T75 cell culture flask from the 37°C 5% CO2 incubator, and use a pipette to aspirate the old culture medium in the flask.

[0493] (3) Aspirate 5 ml of phosphate buffer solution and add it to the culture flask to rinse the cells, then discard the liquid.

[0494] (4) Aspirate 1 ml of trypsin and add it to the culture flask. After shaking, place the culture flask in the incubator.

[0495] (5) After 1 minute, take out the culture flask. After observing that the cells have all detached, aspirate 5 ml of medium and add it to the culture flask, and pipette several times to transfer the cell suspension to a 50 ml centrifuge tube.

[0496] (6) Aspirate 0.7 ml of the cell suspension and add it to the counting cup. Count on the ViCell XR, and then dilute the cell suspension with medium to the cell concentration required for plating: 1000 / 30 μl.

[0497] (7) 2 microporous plates are needed. Add 100 μl of phosphate buffer solution to the peripheral wells of the 384-well plate, and add 30 μL of the cell suspension to the other wells respectively. Then place the cell plate in the incubator for culture.

[0498] 3) Drug addition

[0499] (1) Compound preparation: The stock solution of the compound to be tested is 10 mM.

[0500] (2) Dilute the compound to be tested 10-fold in 3 gradients with DMSO.

[0501] (2) Dilute the compound to be tested with medium, and the highest final concentration is 10 μM.

[0502] (3) Take out the cell plate from the incubator.

[0503] (4) Aspirate 10 μL of the compound into the 384-well plate, and then place the cell plate back into the incubator for culture.

[0504] 4) Add CTG and read the plate

[0505] (1) After culturing for 7 days, add 50 μl of CellTiter Glo to the cell plate, shake it in the dark for 10 minutes, and let it stand at room temperature for 5 minutes.

[0506] (2) Read the plate on the Envision, program: US LUM 384 (CPS). The original experiment is stored in the personal disk:

[0507] Y:\RAW DATA\FL353\CTG-OVCAR3-MCF-7-PR

[0508] Data analysis:

[0509] 1. Calculate the mean and standard deviation of 0% inhibition (DMSO column, ZPE) and 100% inhibition (PBS row, HPE).

[0510] 2. Inhibition rate (%) = (1 - (sample value - mean of 100% inhibition) / (mean of 0% inhibition - mean of 100% inhibition)) * 100;

[0511] 3. The curve is fitted by GraphPad 8.0 software

[0512] Table 2 Antiproliferative activity of the compounds of the examples of the present invention against cells (IC 50 )

[0513] Test compound OVCAR-3 (nM) MCF-7-PR 18 17 11 19 29 98 20 12 53 21 15 9 22 44 50 25 <1 <1

[0514] Experimental conclusion: The compounds of the present invention have significant inhibitory activity against the proliferation of OVCAR-3 and MCF-7-PR cells.

[0515] Experimental Example 3: Pharmacokinetic evaluation of the compounds of the present invention

[0516] Experimental protocols for Compounds 18, 19, and 20

[0517] Test animals

[0518] Healthy adult male CD-1 (ICR) mice used in this study were all purchased from Pinghu Vital River Laboratory Animal Technology Co., Ltd.

[0519] Preparation of drugs

[0520] Preparation of the dosing solution for the oral administration group

[0521] Measure 0.300 mL of the stock solution, vortex for 2 minutes to obtain a homogeneous suspension with a final concentration of 1 mg / mL, and the dosing vehicle is 1% HPMC in water.

[0522] Drug administration

[0523] Two male CD-1 (ICR) mice were gavaged with 5 mg / kg of the test compound.

[0524] Sample collection

[0525] Blood was collected continuously from two animals at each time point. 30 μL of whole blood was collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after drug administration. The whole blood was placed in an anticoagulant tube and centrifuged at 3200 g for 10 minutes at 4 °C to prepare plasma, which was stored at -60 °C or lower. LC / MS-MS was used to determine the drug concentration in plasma.

[0526] Table 3 Pharmacokinetic results of the compounds in the examples of the present invention

[0527]

[0528] Experimental conclusion: The compounds of the present invention have high exposure in mice and exhibit good pharmacokinetic properties.

[0529] Experimental Example 4: In vivo pharmacodynamic study

[0530] In vivo pharmacodynamic study on the BALB / c nude mouse model of subcutaneous xenograft tumor of human ovarian cancer OVCAR-3 cells

[0531] Experimental operation:

[0532] Cell culture: Human ovarian cancer OVCAR-3 cells were cultured in vitro in monolayers under the conditions of adding 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin to RPMI 1640 medium, and cultured in an incubator at 37 °C with 5% CO2. Routine digestion and passage were carried out with trypsin-EDTA. When the cell saturation reached 80%-90% and the number reached the requirement, the cells were collected, counted and inoculated.

[0533] Animals: BALB / c nude mice, female, 6-8 weeks old, weighing 18-22 grams. A total of 95 mice (42 + 53 spare) were provided by the Experimental Animal Business Department of Shanghai Institute of Planned Parenthood Research (formerly Shanghai SIPPR / BK).

[0534] Tumor inoculation: 0.2 mL (1×10 7 cells) of OVCAR-3 cells (added with Matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse. When the average tumor volume reached about 150 mm 3 , grouping and drug administration were started.

[0535] Drug administration dose and frequency: From day 0 to day 7, 10 mg / kg; from day 7 to day 14, 10 mg / kg; from day 14 to day 21, 30 mg / kg;

[0536] Experimental indicators: The experimental indicators were to examine whether tumor growth was inhibited, delayed or cured. The tumor diameter was measured twice a week with a vernier caliper. The calculation formula for tumor volume was: V = 0.5a×b 2 , where a and b represent the long diameter and short diameter of the tumor respectively.

[0537] The experimental results are shown in Table 4.

[0538] Table 4 In vivo pharmacodynamic experimental results of the compounds in the examples of the present invention on OVCAR-3

[0539]

[0540] Experimental conclusion:

[0541] In the in vivo pharmacodynamic study of the human ovarian cancer OVCAR-3 cell subcutaneous xenograft tumor BALB / c nude mouse model, the animals tolerated the compounds of the present invention well, showing good pharmacodynamic effects and safety.

Claims

1. The compound shown in formula (III) or a pharmaceutically acceptable salt thereof, wherein, Ring A is a 3- to 10-membered heterocycloalkyl group, and the 3- to 10-membered heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3 Rs a substituted; W is selected from and R5; Ring B is selected from C 3～8 cycloalkyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl, and said C 3～8 cycloalkyl, 5- to 6-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R b substituents; X is C(R c )); Y is selected from a single bond, -NH-, and -O-; L is -S(=O)2-; R1 is selected from H, halogen, C 1～3 alkyl, C 1～3 alkoxy and -C(=O)-C 1～3 alkyl, wherein the C 1～3 alkyl, C 1～3 alkoxy and -C(=O)-C 1～3 alkyl are each independently optionally substituted by 1, 2 or 3 R d substituents; R2 and R3 are each independently selected from H, halogen, OH, CN, NH2 and C 1～8 alkyl, and the C 1～8 alkyl is optionally substituted with 1, 2 or 3 R e substituents; R4 is selected from NH2, -NH-C 1～6 alkyl, -NH(CN), -NH(OH), C 1～6 alkyl, -N(CN)-C 1～6 alkyl, and -N(OH)-C 1～6 alkyl, wherein the -NH-C 1～6 alkyl, C 1-6 alkyl, -N(CN)-C 1～6 alkyl, and -N(OH)-C 1～6 alkyl are each independently optionally substituted by 1, 2 or 3 R f substituents; R5 is selected from C alkyl optionally substituted by 1, 2 or 3 Rs g alkyl 1～3 optionally substituted by 1, 2 or 3 Rs R c selected from H, F, Cl, Br, I, and CH3; R d each independently selected from F, Cl, Br, I, CH3, OCH3, OH, NH2, CN, COOH; R a 、R b 、R e and R f are each independently selected from F, Cl, Br, I, OH, CN, CH3, CH3CH2, CH3CH2CH2, CH(CH3)2, OCH3, OCF3, CHF2, CH2F, and NH2; R g each independently selected from F, Cl, Br, I, OH, CN, and CH3; The 3- to 10-membered heteroalkyl group and the 5- to 6-membered heteroaryl group each contain 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from H, Cl, CHF2, CF3 and CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 and R3 are each independently selected from H, F, Cl, OH and CH3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R4 is selected from CH3, NH2 and -NH(CH3).

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, X is selected from CH, CF, CCl, CBr, CCH3 and N.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 5- to 6-membered heterocycloalkyl, and the 5- to 6-membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R a substituents.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from piperidinyl, which is optionally substituted with 1, 2 or 3 R a substituents.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein, Ring A is selected from 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from C 5～6 cycloalkyl, 5- to 6-membered heteroalkyl, and 5- to 6-membered heteroaryl, wherein said C 5～6 cycloalkyl, 5- to 6-membered heteroalkyl, and 5- to 6-membered heteroaryl are each independently optionally substituted with 1, 2, or 3 R b substituents.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from cyclopentyl, pyrrolidinyl, and pyrazolyl, and the cyclopentyl, pyrrolidinyl, and pyrazolyl are each independently optionally substituted with 1, 2, or 3 Rs b substituents.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from 12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The structural unit -Y-W is selected from 13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein, The structural unit -Y-W is selected from 14. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Structural unit Selected from 15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R5 is selected from 16. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from wherein, R1, R2, R3, R4, R5, X, Y and ring A are as defined in claims 1 to 15.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from wherein, R1, R2, R3, R4, R5 and R c as defined in claim 16.

18. A compound or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from 19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein, The compounds are selected from 20. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein, The compounds are selected from 21. Use of the compound according to any one of claims 1 to 20 in the preparation of a medicament for treating breast cancer.

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